Title of Invention

CALCIUM CHANNEL BLOCKERS

Abstract The present invention is directed in part towards methods of modulating the function of calcium channels with dihy-dropyrimidine, dihydropyrimidone, dihydropyrimidinethione, and dihydropyridine compounds. In addition, the invention describes methods of preventing and treating protein kinase-related abnormal conditions in organisms with a compound identified by the invention. Furthermore, the invention pertains to T-channel agonists that have a slow onset of activity and long duration of activity.
Full Text Background of the Invention
Field of the Invention
[0001] The present invention relates to certain dihydropyriinidine,
dihydropyrimidone, dihydropyrimidinethione, and dihydropyridine compounds that can modulate
the activity of calcium channels. These compounds can also be used for the treatment of diseases,
such as cardiovascular disease, that are associated with calcium channels.
Description of the Related Art
[0002] The pharmacological function and importance of calcium antagonists or
calcium channel blockers, has been well documented. See, for example, R. A. Janis and D. J.
Triggle "New developments in Ca2*channel antagonists" Journal of Medicinal Chemistry, 26, 775-
785 (1983). Among the calcium antagonists, 4-aryl-l,4^imydropyridine-3,5-dicarboxylic diesters
(DHPs) of the nifedipine type have become almost indispensable for the treatment of
cardiovascular diseases. For a review on Structure Activity Relations (SAR) see, S. Goldmann and
J. Stoltejuss "1,4-Dihydropyridine: Effects of chirality and conformation on the calcium antagonist
and calcium agonist activities" Angewandte Chemie International Edition (English) 30,1559-1578
(1991). It was well documented mat substitution on 4-phenyl ring is very crucial for
pharmacological activity. Substituents at ortho or meta position improve the activity, whereas para
substitution invariably decrease the activity. It was also published that buMness of ortho
substituent, improves the calcium antagonist activity. B. Loev, M. M. Goodman, K. M. Snader, R.
Tedeschi,E. Macko, " Hantzsch-Type Dihydropyridine hypotensive Agents ", Journal of Medicinal
Chemistry 17, 956-965 (1974).
[0003] Voltage-gated calcium channels are large transmembrane proteins that regulate
the intracellular concentration of calcium ions. They are classified into high (HVA) and low (LVA)
voltage-activated channels according to the membrane potential at which they are activated. E.
Carbone and H. D. Lux . "A low voltage activated, fully inactivating Ca channel in vertebrate
sensory neurons" Nature, 310, 501-502, (1984): B. Nilius , P. Hess, J. BJLansman and R.
W.Tsien A novel type of cardiac calcium channel in ventricular cells. Nature, 316, 443-446.
(1985).; M. C.Nowycky, A. P. Fox , R. W. Tsien. "Three types of neuronal calcium channels with
different calcium agonist sensitivity" Nature 316, 440-443 (1985). LVA channels open and
inactivate very fast, but deactivate about 10-100 times slower man HVA calcium channels. HVA
channels require stronger membrane depolarizations to activate and can be divided further into N,
P/Q.R and L-types based on their pharmacological properties. LVA channels can be detected in
various tissues such as heart, brain, dorsal root ganglia and adrenal gland. The use of different
search algorithms on mammalian expressed sequence tagged cDNAs or on similar sequences of the
nematode Caenorhabditis elegans led to the identification of several genes, three of which encoded
LVA calcium channels (T-type channels) and they have been named as ccjg. ciih, an; see Review,.
L. Lacinova, N. Klugbauer, F.Hofmann "Low voltage activated calcium channels: from genes to
function" Gen. Physiol. Biophys., 19, 121-136, (2000). Of the above stated types of calcium
channels, L-type channels received wide attention. Among the L-type channel blockers,
Dihydropyridines (DHP) is the most widely studied. But, most of the DHPs are not selective
against T-type channels and DHPs inhibiting the T-type channels is still sparse.
[0004] Voltage-gated calcium channels are important regulators of calcium influx in a
number of cell types. Calcium entry through these channels activates a plethora of intracellular
events, from the broad stimulation of gene expression, calcium-dependent second messenger
cascades, and cell proliferation, to the specific release of neurotransmitter within the nervous
system, and contraction in smooth and cardiac muscle (Tsien et al., 1988)(Wheeler et al, 1994);
(Dunlap et al., 1995); (Tsien et al., 1991). A number of different types of calcium channels have
been identified in native tissues and divided based on their biophysical profiles into low voltage
activated (LVA) and high voltage activated (HVA) channels (Nowycky et al., 1985); (Tsien et aL,
1991). LVA channels first activate at relatively hyperpolarized potentials and rapidly inactivate
(Akaike et al, 1989); (Takahashi et al, 1991). By contrast, HVA channels require stronger
membrane depolarizations to activate and can be divided further into N, P/Q-, R and L-types based
on their pharmacological properties (for review, see (Stea et al, 1995); (Zamponi, 1997)).
Molecular cloning has revealed that HVA channels are heteromultirners comprised of a pore
forming ai subunit plus ancillary ar£, P and possibly y subunits (Pragnell et al, 1994);
(Klugbauer et al, 1999); (Klugbauer et al, 2000); for review, see (Catterall, 2000), whereas LVA
channels appear to contain only the a.\ subunit (Lacinova et al, 2000)). To date, ten different types
of calcium channel ai subunits have been identified and shown to encode the previously identified
native calcium channel isoforms. Expression studies show that alternative splicing of aXA generates
both P- and Q-type Ca2+ channels (Bourinet et al., 1999), am encodes N-type channels (Dubel et
al, 1992)) a,c, a1D and a1F are L-type channels (Williams et al., 1992b); (Bech-Hansen et al,
1998), aio, a1H and an form T-type channels (i.e., McRory et al., 2001) and aiE may encode R-type
channels (Soong et al, 1993); (Tottene et al, 1996), and a,s encodes the skeletal muscle L-type
channel isoform (Tanabe et al, 1987).
[0005] Dihydropyridine (DHP) antagonists of L-type calcium channels are widely
used therapeutics in the treatment of hypertension, angina, arrhythmias, congestive heart failure,
cardiomyopathy, atheriosclerosis, and cerebral and peripheral vascular disorders (Janis and Triggle,
1990) CRC Press, Cleveland. DHPs having a tendency to selectively block and enhance native L-
type calcium channel activity. B. P.(Bean, 1984).; B. .Z (Peterson and Catterall, 1995). Jh addition
to L-type channel activity, some of the DHPs are sensitive to T-type channel activity. (N. Akaifce, H.
Kanaide, T, Kuga, M, Nakamura, J. Sadoshima and Tomoike "Low Voltage Activated Calcium
Current in rat Aorta Smooth Muscle Cells In Primary Cultur" J Physiol. 416,141-160, (1989).

where A is selected from the group consisting of oxygen, sulfur,
and -NH and RM is selected for the group consisting of hydrogen,
hydroxy, alkoxy, haloalkoxy, halogen, haloalkyl, perhaloalkyl,
nitro, amino, and a diazo salt, and n is between 0-4; and
where the ring moieties are each independently and optionally substituted
with one or more substituents selected from the group consisting of lower
alkyl, lower alkylene,
b) R9 is selected from the group consisting of hydrogen, alkyl, alkylene, and a five-
membered or six-membered heteroaryl ring or a six-membered aryl or heteroaryl
ring, optionally substituted with one or more substituents selected from the group
consisting of lower alkyl, lower alkylene, halogen, perhaloalkyl, nitro, amino,
cyano, amido, and ester; and
c) R10 is selected from the group consisting of hydrogen and lower alkyl, or that R10 is
optionally not present, in which case the nitrogen-containing ring in the compound
of Formula I is an aromatic pyridine.
[0007] Furthermore, disclosed are compounds of Formula II

A is selected from the group consisting of oxygen, sulfur, sulfoxide,
sulfone, and -NH;
R22 is selected from the group consisting of hydrogen, hydroxy, alkoxy,
haloalkoxy, halogen, haloalkyl, perhaloalkyl, nitro, amino, and a diazo salt;
n is between 0-4; and
said ring moieties are each independently and optionally substituted with
one or more substituents selected from the group consisting of lower alkyl,
lower alkylene,
b) RI9 is selected from the group consisting of hydrogen, alkyl, alkylene, and a five-
membered or six-membered heteroaryl ring or a six-membered aryl or heteroaryl
ring, optionally substituted with one or more substituents selected from the group
consisting of lower alkyl, lower alkylene, halogen, perhaloalkyl, nitro, amino,
cyano, amido, and ester; and
c) R20 is selected from the group consisting of hydrogen and lower alkyl
d) R21 is selected from the group consisting of:
i) hydrogen, alkyl, alkoxy, alkylene, and a five-membered or six-membered
heteroaryl ring or a six-membered aryl or heteroaryl ring, optionally
substituted with one or more substituents selected from the group
consisting of lower alkyl, lower alkylene, halogen, perhaloalkyl, nitro,
amino, cyano, amido, and ester,
ii) COY wherein Y is C1-C8 alkyl, C1-C8 alkoxy or NR13R14, wherein R13 is
hydrogen or C1-C8 alkyl and R14 is hydrogen, C1-C8 alkyl, or C1-C14
phenalkyl;

iv) halogen, CF3, cyano, nitro, COONHR35, COON(R3S)2, COOSO2R38,
COONR35SO2N(R-35)2 CO2R35, COON(R35)2, COOSO2N(R35)2,
COOS02R38.
v) CONR25R26, wherein R25 is selected from the group consisting, of
hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl and R26 is selected from the
group consisting of hydrogen, alkyl, cycloalkyl, aryl, or halosubstituted
alkyl, or R25 and R26 taken together with the nitrogen atom to which they
are attached form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl,
4-thiamorpholinyl, 1-piperazinyl, 4-diarylalkyl-l-piperazinyl, each of
which is optionally substituted with one or more substituents selected from
the group consisting of alkyl, alkoxy, alkylthio, halo, trifloromethyl, or
hydroxy;
vi) Z, COOZ, or C(0)(NH)Z, wherein Z is selected from the group consisting
of

wherein
A) p and q are each independently 0-10;
B) R30 is phenyl optionally substituted with one or more substituents
independently selected from the group consisting of halogen, CF3,
cyano, nitro, N(R3S)2, NR35CONR37, NR35CON(R37)2, NR3SS02R38,
NR35S02N(R37)2, (Ca2)*4CO2R3s, (CH2)0-4CON(R35)2, (CH2)0-
4SO2N(R35)2, (CH2)0-4SO2R38, and C1-4 alkyl;
C) R31 is selected from the group consisting of hydrogen, cyano,
OR38, COOR3S, CON(R35)2, and phenyl optionally substituted with
one or more substituents independently selected from the group
consisting of halogen, CF3, cyano, nitro, N(R35)2, NR35CONR37,
NR35CON(R37)2, NR35SO2R38, NR3SS02N(R37)2, (CH2)0-4mCO2R35,
(CH2),mCON(R35)2, (CH2)0-4SO2NCR35)2, (CH2)0-1-4SO2R38, and C1-4
alkyl;
D) R35 and R37 are each independently selected from hydrogen, C1-8
alkyl, C3-8 cycloalkyl, (CH2)0-4CF3; and
E) R38 is selected from the group consisting of hydrogen, C1-8 alkyl.
Cw cycloalkyl, and (CH2) e) X is oxygen or sulfur, and
f) Q is oxygen or nitrogen; provided that when Q is oxygen R)3 does not exist
[0008] Also disclosed is a method of modulating the activity of a calcium channel in a
cell comprising the step of contacting the cell with a compound as described above.
[0009] In addition, disclosed is a method of treating a disease associated with a
cellular calcium channel comprising identifying a subject in need of such treatment; and
administering to the subject a therapeutically effective amount of a compound as described above.
[0010] Also disclosed is a method for inhibiting calcium T-chanriel activity,
comprising the steps of providing a selective T-channel antagonist having an onset of activity in
reducing systolic blood pressure in vivo of at least three hours and a duration of activity in vivo of
at least 24 hours, where onset of activity refers to the time from administration to maximum
reduction of systolic blood pressure, and duration of activity refers to the time from administration
until the maximum amount of systolic blood pressure reduction achieved subsequently decreases
by at least 20 percent; and administering the antagonist to a mammal in regular doses no more
often than once per day.
[0011] Furthermore, a method for treating hypertension is disclosed, which method
comprises repeatedly administering to a patient a selective T-channel antagonist in individual
dosages spaced at least one day apart.
[0012] In addition, disclosed is a method for selecting calcium T-channel antagonists
having a desired pharmacological profile, comprising testing candidate compounds to measure
rapidity of onset of activity; testing candidate compounds to measure duration of activity; and
selecting candidate compounds having a slower onset of activity and a longer duration of activity
than mibefradil.
[0013] Furthermore, pharmaceutical compositions are disclosed comprising a
compound as described above, and a physiologically acceptable carrier, diluent, or excipient, or a
combination thereof.
Brief Description of the Drawings
[0014] Figure 1 shows the single dose efficacy in spontaneously hypertensive rats,
comparing PPK-5, Amlodipine, and Mibefradil.
[0015] Figure 2 shows a multiple daily dose efficacy in spontaneously hypertensive
rats, comparing PPK-5 and Mibefradil.
Detailed Description of the Preferred Embodiment
alkoxy-6,-pentadecylphenyl)-2,6-dimefliyl-3,5.-pyridine dicarboxylates) derived from anacardic
acid, a phenolic constituent present in cashew nut shell liquid (Paul and Yeddanapalli, 1956),
(1956). These compounds exhibit activity as calcium channel antagonists, and can be used for the
various purposes for which these types of compounds are known.
I. Compounds of the Invention
[0017] Thus, an aspect of the present invention relates to a compound of Formula I
or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof,
where
a) R1-R8 are each independently selected from the group consisting of
hydrogen;,halogen, perhaloalkyl, nitro, amino, a diazo salt, optionally substituted
lower alkyl, optionally substituted lower alkylene and optionally substituted five-
membered or optionally substituted six-membered heteroaryl ring or optionally
substituted six-membered aryl or heteroaryl ring,
where the lower alkyl and the lower alkylene moieties are each
independently and optionally substituted with one or more substituents
selected from the group consisting of halogen, perhaloalkyl, nitro, amino,
hydroxy, alkoxy, sulfhydryl, thioether, cyano, amido, ester, and

where A is selected from the group consisting of oxygen, sulfur,
and -NH and R11 is selected for the group consisting of hydrogen,
hydroxy, alkoxy, haloalkoxy, halogen, haloalkyl, perhaloalkyl,
nitro, amino, and a diazo salt, and n is between 0-4; and
where the ring moieties are each independently and optionally substituted
with one or more substituents selected from the group consisting of lower
alkyl, lower alkylene,
b) R9 is selected from the group consisting of hydrogen, alkyl, alkylene, and a five-
membered or six-membered heteroaryl ring or a six-membered aryl or heteroaryl
ring, optionally substituted with one or more substituents selected from the group
consisting of lower alkyl, lower alkylene, halogen, perhaloalkyl, nitro, amino,
cyano, amido, and ester; and
c) R10 is selected from the group consisting of hydrogen and lower alkyl, or that R10 is
optionally not present, in which case the nitrogen-containing ring in the compound
of Formula I is pyridine.
[00181 The term "pharmaceutically acceptable salt" refers to a formulation of a
compound that does not cause significant irritation to an organism to which it is administered and
does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can
be obtained by reacting a compound of the invention with inorganic acids such as'hydrochloric
acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid,
ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Pharmaceutical salts can
also be obtained by reacting a compound of the invention with a base to form a salt such as an
ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal
salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-
methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as
arginine, lysine, and the like.
[0019] The term "ester" refers to a chemical moiety with formula -(R)„-COOR',
where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl,
heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and
where n is 0 or 1.
[0020] An "amide" is a chemical moiety with formula -(R)n-C(0)NHR' or
-(RX-NHC(0)R\ where R and R* are independently selected from the group consisting of alkyl,
cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a
ring carbon), and where n is 0 or 1. An amide may be an amino acid or a peptide molecule attached
to a molecule of the present invention, thereby forming a prodrug.
[0021] Any amine, hydroxy, or carboxyl side chain on the compounds of the present
invention can be esterified or amidified. The procedures and specific groups to be used to achieve
this end is known to those of skill in the art and can readily be found in reference sources such as
Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York,
NY, 1999.
[0022] A "prodrug" refers to an agent mat is converted into the parent drug in vivo.
Prodrugs are often useful because, in some situations, they may be easier to administer than die
parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is
not. The prodrug..may^also> have improved solubility in pharmaceutical compositions over the
parent drug. An example, without limitation, of a prodrug would be a compound of the present
invention which is administered as an ester (the "prodrug") to facilitate transmittal across a cell
membrane where water solubility is detrimental to mobility but which then is metabolically
hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is
beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an
acid group where the peptide is metabolized to reveal the active moiety.
[0023] The term "aromatic" refers to an aromatic group which has at least one ring
having a conjugated pi electron system and includes both carbocyclic aryl (e.g., phenyl) and
heterocyclic aryl groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic
(i.e., rings which share adjacent pairs of carbon atoms) groups. The term "carbocyclic" refers to a
compound which contains one or more covalently closed ring structures, and that the atoms
forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic
from heterocyclic rings in which the ring backbone contains at least one atom which is different
from carbon. The term "heteroaromatic" refers to an aromatic group which contains at least one
heterocyclic ring.
[0024] As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group. The
alkyl moiety may be a "saturated alkyl" group, which means that it does not contain any alkene or
alkyne moieties. The alkyl moiety may also be an "unsaturated alkyl" moiety, which means that it
contains at least one alkene or alkyne moiety. An "alkene" moiety refers to a group consisting of at
least two carbon atoms and at least one carbon-carbon double bond, and an "alkyne" moiety refers
to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The
alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.
[0025] The alkyl group may have 1 to 40 carbon atoms (whenever it appears herein, a
numerical range such as "1 to 40" refers to each integer in the given range; e.g., "1 to 40 carbon
atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms,
etc., up to and including 40 carbon atoms, although the present definition also covers the
occurrence of the term "alkyl" where no numerical range is designated). The alkyl group may also
be a medium size alkyl having 1 to 20 carbon atoms. The alkyl group could also be a lower alkyl
having 1 to 5 carbon atoms. The alkyl group of the compounds of the invention may be designated
as "C1-C4 alkyl" or similar designations. By way of example only, "C1-C4 alkyl" indicates that
there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group
consisting of methyl, ethly, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
[0026] The alkyl group may be substituted or unsubstituted. When substituted, the
substituent group(s) is(are) one or more group(s) individually and independently selected from
cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio,
cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,
C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato,
thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and
di-substituted amino groups, and the protected derivatives thereof. Typical alkyl groups include,
but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl,
hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
Wherever a substituent is described as being "optionally substituted" that substituent may be
substituted with one of the above substituents.
[0027] The substituent "R" appearing by itself and without a number designation
refers to a substituent selected from the group consisting of of alkyl, cycloalkyl, aryl, heteroaryl
(bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
[0028] An "O-carboxy" group refers to a RC(=0)0- group, where R is as defined
herein.
[0029] A "C-carboxy" group refers to a -C(=O)OR groups where R is as defined
herein.
[0030] An "acetyl" group refers to a -C(=O)CH3, group.
[0031] A "trihaloraethanesulfonyl" group refers to a X3CS(=O)2- group where X is a
halogen.
[0032] A "cyano" group refers to a -CN group.
[0033] An "isocyanato" group refers to a -NCO group.
[0034] A "thiocyanato" group refers to a -CNS group.
[0035] An "isothiocyanato" group refers to a -NCS group.
[0036] A "sulfinyr group refers to a -S(=O)-R group, with R as defined herein.
[0037] A "S-sulfonamido" group refers to a -S(=O)2NR, group, with R as defined
herein.
[0038] A "N-sulfonamido" group refers to a RS(=O)2NH- group with R as defined
herein.
[0039] A "trihalomethanesulfonarnido" group refers to a X3CS(=O)2NR- group with
X and R as defined herein.
[0040] An "O-carbamyl" group refers to a -OC(=O)-NR, group-with R as defined
herein.
[0041] An "N-carbamyr group refers to a ROC(=O)NH- group, with R as defined
herein.
[0042] An "O-thiocarbamyl" group refers to a -OC(=S)-NR, group with R as defined
herein.
[0043] An "N-thiocarbamyr group refers to an ROC(=S)NH- group, with R as
defined herein.
[0044] A "C-amido" group refers to a -C(=6)-NR2 group with R as defined herein.
[0045] An "N-amido" group refers to a RC(=O)NH- group, with R as defined herein.
[0046] The term "perhaloalkyl" refers to an alkyl group where all of the hydrogen
atoms are replaced by halogen atoms.
[0047] Unless otherwise indicated, when a substituent is deemed to be "optionally
subsituted," it is meant that the subsitutent is a group that may be substituted with one or more
group(s) individually and independently selected from cycloalkyl, aryl, heteroaryl, heteroalicyclic,
hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-
carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,
N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl,
trihalomethanesulfonyl, and amino, including mono- and di-subsrituted amino groups, and the
protected derivatives thereof. The protecting groups that may form the protective derivatives of the
above substituents are known to those of skill in the art and may be found in references such as
Greene and Wuts, above.
[0048] In certain embodiments, in the compound of Formula I, wherein R1 and R4 may
each independently be hydrogen or lower alkyl. In other embodiments, R1 and R4 may be lower
alkyl. The lower alkyl may optionally and independently be selected from the group consisting of
methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and pentyl. In some embodiments,
R1 and R4 are methyl.
[0049] Certain embodiments of the invention relate to a compound of Formula I,
where R2 and R3 may each independently be hydrogen or lower alkyl. In other embodiments, R2
and R3 may be lower alkyl. The lower alkyl may optionally and independently be selected from the
group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and pentyl. In
certain embodiments R2 may be methyl, while in other embodiments R2 may be ethyl. In some
embodiments R3 may be isopropyl, while in other embodiments R3 may be methyl, and in still other
embodiments R3 may be isopropyl.
[0050] In some embodiments, R$ of the compound' of Formula I may be hydrogen or
lower alkyl. In certain embodiments, R5 may be lower alkyl. The lower alkyl may optionally and
independently be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl,
sec-butyl, tert-butyl, and pentyl. In certain embodiments Rs may be methyl, while in other
embodiments Rj may be ethyl or isopropyl.
[0051] The R«-Rs substituents of the compound of Formula I may in some
embodiments each be independently hydrogen or lower alkyl. hi certain embodiments, Rs-R« are
hydrogen.
[0052] Some embodiments relate to a compound of Formula I in which R9 is hydrogen
or alkyl. In certain embodiments, R9 may be alkyl. In some embodiments R9 may be a straight
chain alkyl while in omer embodiments R9 may be a branched alkyl. R9 may comprise at least 30,
or 20, or 15, or 10, or 8, or 5, or at least 3 carbon atoms. In some embodiments R, is pentadecyl,
which has the formula -CH2(CH2)i3CH3.
[0053] The substituent R,0 may be present or may be absent In some embodiments
Rio is present and is hydrogen. In other embodiments R10 is absent and the nitrogen containing ring
in the compound of Formula I is an aromatic pyridine. Those of skill in the art understand that
when R,0 is present, to position 4 of the nitrogen-containing ring, i.e., the position to which the
phenyl group is attached, an additional hydrogen, not shown in the above formula, is connected.
Thus, there are four single bonds to the carbon of position four: two bonds within a ring, one bond
to the phenyl group, and one bond to the hydrogen (not shown). However, when R,0 is absent, no
hydrogen is attached to the carbon of position 4. The phenyl group would be the only group
attached to that carbon, in addition to the bonds within the ring.

selected from the group consisting of oxygen, sulfur, and -NH and R11 is selected from the group
consisting of hydrogen, hydroxy, alkoxy, haloalkoxy, halogen, haloalkyl, perhaloalkyl, nitro,
amino, and a diazo salt, and n is between 0-4.
[0055] A "diazo salt" is a group of formula -NN X", where X is a halogen. In some
embodiments, the halogen is a chlorine, while in other embodiments, the halogen is a fluorine, or a
bromine.
[0056] hi some embodiments A is oxygen, while in other embodiments A is sulfur,
and in still other embodiments A is -NH.
[0057] In certain embodiments, R11 is hydrogen.
[0058] In certain embodiments, the present invention relates to a compound of
Formula I, where the compound is selected from the group consisting of
diethyl 1,4-dihydro-4-(2'-eraoxy-6,-pentadecylphenyl)-2,6-dimeaiyl-3,5-pyridine
dicarboxylate;
dimethyl 1,4-dmydro-4-(2'-emoxy-6'-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine
dicarboxylate;
diisopropyl 1,4-dihydro-4^2'-emoxy-6,-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine
dicarboxylate;
diethyl 1,4-dihydro-4-(2'-memoxy-6'-rjentadecylphenyl)-2,6^imeuiyI-3,5-pyriduie
dicarboxylate;
dimethyl 1,4-dihydrc-4-(2'Hmemoxy^'-pentadecyIphenyl)-2,6-dimethyl-3>5-pyridine
dicarboxylate;
diisopropyl 1,4-dmydro-4-pentadecylphenyl)-2,6^imemyl-3,5-
carboxypyridine dicarboxylate;
diethyl I,4-dmydro-4 dicarboxylate;
dimethyl 1,4^ihydro-4-(2^isopropoxy-6'-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine
dicarboxylate; ,
diisopropyl 1,4-dmydro-4-(2'-isopropoxy-6'-pentadecylphenyl)-2,6-dimethyI-3,5-pyridnie
dicarboxylate;
diethyl 1,4^mydrc^-(2'-rnemoxy-6,i)entadecylphenyl)-2-riKmyl-6H2'-mercapto-l'H-
benzimidazolyl)methyl-3,5-pyridine dicarboxylate;
dimethyl 1,4-dihydro-4-(2' -methoxy-6' -pentadecylphenyl)-2-methyl-6-(2' -mercapto-1 'H-
benzimidazolyl)methyl-3,5*pyridine dicarboxylate;
diisopropyl 1,4-dihydro-4-(2'-methoxy-6'-pentadecylphenyl)-2-methyl-6-(2'-mercapto-
1 'H-benzimidazolyl)methyl-3,5- pyridine dicarboxylate;
diethyl 1,4-dihydro-4-(2'-isopropoxy-6'-pentadecylphenyl)-2-methyl-6-(2'-mercapto-rH-
benzimidazolyl)methyl-3,5-pyridine dicarboxylate;
dimethyl 1,4-dihydro-4-(2'-isopropoxy-6,-pentadecylphenyl)-2-methyl-6-(2'-mercapto-
1 'H-benzimidazoly^methyl-S.S- pyridine dicarboxylate;
diisopropyl l^ihydro^^'-isopropoxy-^'-pentadecylpheny^^-methyl-e^'-mercapto-
1 ,H-benzimidazolyl)methyl-3,5-pyridine dicarboxylate;
diethyl 1,4-clihydro-4-(2'-ethoxy-6,-pentadecylphenyl)-2-methyl-6-(2'-mercapto-l 'H-
benzimidazolyl)methyl -3,5-pyridine dicarboxylate;
dimethyl 1,4-dihydro-4-(2'-ethoxy-6'-pentadecylphenyl)-2-methyl-6-(2'-mercapto-l 'H-
benzimidazolyl)methyl-3,5- pyridine dicarboxylate;
diisopropyl l)4-dihydro-4-(2'-ethoxy-6'-pentadecylphenyl)-2-methyl-6-(2'-rnercapto-rH-
benzimidazolyl)methyl-3,5-pyridine dicarboxylate;
1,4^1mydro-4^2'^Aoxy^'-pentadecylphenyl)-2,6^imethyl-3-ethyl-5-
(methoxyethyl)pyridine dicarboxylate;
1,4^imydro-4-(2'-ethoxy-6'-pentadecylphenyl)-2,6-dimetb.yl-3-methyl-5-
(methoxyethyl)pyridine dicarboxylate;
1,4-dihydro-4-(2'-ethoxy-6,-pentadecylphenyl)-2,6-dimethyl-3-isopropyl-5-
(methoxyethyl)pyridine dicarboxylate;
1,4-^mydr6^4^2'-memoxy^'-pentadecylphenyl)-2,6^imethyl-3-ethyI-5-
(methoxyethyl)pyridine dicarboxylate;
1,4-dihydro-4-(2'-isopropoxy-6'-pentadecylphenyl)-2,6-dimethyl-3-ethyl-5-
(rnethoxyethyl)pyridine dicarboxylate;
diethyl 1,4-dihydro-4-(2 '-ethoxy-6 '-pentadecylphenyl)-2-(2 '-aminoethoxy)methyl-6-
methyl-3,5-pyridine dicarboxylate;
dimefhyl 1,4-dmydro^2'^moxy^,-pentadecylphenyl>2 methyl-3,5-pyridine dicarboxylate;
diisopropyl 1,4-dmydro^2'^moxy^'-pentade2^2'-arninoethoxy)methyl-6-
methyl-3,5-pyridine dicarboxylate;
diemyl1,4-dmydrcMK2,-methoxy^'-pentadecylphenyl)-2^2'-aminoethoxy)memyl-6-
methyl-3,5-pyridine dicarboxylate;
dimethyl 1,4-dihydro-4- (2'-methoxy-6'-pentadecylphenyl)-2-(2'-aminoethoxy)methyl-6-
methyl-3,5-pyridine dicarboxylate;
diisopropyl 1,4^ihydro^-(2'-methoxy-6'-pentadecylphenyl)-2-(2'-aminoethoxy)methyl-6-
methyl-3,5-pyridine dicarboxylate;
diethyl 1,4-dihydro-4-(2' -isopropoxy-6 '-pentadecylphenyl)-2-((2 '-aminoethoxy)methyl-6-
methyl-3,5-pyridine dicarboxylate;
dimethyl 1,4-dihydro-4-(2'-isbpropoxy-6'-pentadecylphenyl)-2-(2'-aminoethoxy)methyl-6-
methyl-3,5-pyridine dicarboxylate;
diisopropyl 1,4H3ihydro^-(2'-isopropoxy^'-pentedecylphenyl)-2-(2'-aminoethoxy)methyl-
6-methyl-3,5-pyridine dicarboxylate;
pyridine dicarboxylate;
dimethyl 1,4-dihydro-4-(2'-ethoxy-3',5'-diiiitro-6'-pentadecylphenyl)-2,6-dimethy1-3,5-
pyridine dicarboxylate;
diisopropyl 1,4-dihydro-4-(2'-ethoxy-3',5'-dinitro-6'-pentadecylphenyl)-2,6-dimethyl-3,5-
pyridine dicarboxylate;
diethyl 1,4-dihydro-4-(2'-memoxy-3\5,-dmitro-6'-pentadecylphenyl)-2,6^dimethyl-3,5-
pyridine dicarboxylate;
dimethyl 1,4-dihydto-4-(2'-memoxy-3\5'-dmitro-6'i)entadecylphenyl)-2,6^imethyl-3,5-
pyridine dicarboxylate;
diisopropyl 1,4-dihydro-4-(2'-methoxy-3',5'-dinitro-6'-pentadecylphenyl)-2,6-dimethyl-
3,5-pyridine dicarboxylate;
diemyl1,4-dihydro-4-(2'-isopropoxy-3',5'-dintro-6'entadecylphenyl)-2,6-dimethyl-3,5-
pyridine dicarboxylate;
dimethyl 1,4-dmydro-4-(2'-isopropoxy-3',5,-dinitro-6'-pentadecylphenyI)-2,6-dimethyi-
3,5-pyridine dicarboxylate;
diisopropyl 1,4-dihydro-4-(2,-isopropoxy-3,5'-dinitro-6,-pentadecylphenyl)-2,6-dimethyl-
3,5-pyridine dicarboxylate;
diethyl 1,4-dihydro-4-(2'-ethoxy-3',5'-diarnino-6'-pentadecylphenyl)-2,6-dimethyl-3,5-
pyridine dicarboxylate;
dimethyl 1,4^ihydro-4-(2'-emoxy-3^5'-diamirio-6'-pentadecylphenyl)-2,6-dimethyl-3,5-
pyridine dicarboxylate;
diisopropyl 1,4-dihydro-4-(2'-emoxy-3\5'-dkmmo-6'i)entadecylphenyl)-2,6-dimethyl-
3,5-pyridine dicarboxylate;
pyridine dicarboxylate;
dimemyl1,4-dmydro-4-(2'-memoxy-3\5'-diammo-6,-rwntadecylphenyl)-2,6^irnemyl-3,5-
pyridine dicarboxylate;
diisopropyl 1,4-dihydro-4-(2' -methoxy-3' ,5' -diamino-6' -pentadecylphenyl)-2,6-dimethyl-
3,5-pyridine dicarboxylate;
diethyl 1,4-dihydro-4-(2'-isopropoxy-3'55'-diamino-6'-pentadecylphenyl)-2,6-dimethyl-
3,5-pyridine dicarboxylate;
dimethyl 1,4-dihydro-4-(2'-isopropoxy-3',5'-diamino-6'-pentadecylphenyl)-2,6-dimethyl-
3,5-pyridine dicarboxylate;
diisopropyl 1,4-dihydro-4-(2'-isopropoxy-3',5'-diamino-6'-pentadecylphenyl)-2,6-
dimethyl-3,5-pyridine dicarboxylate;
diethyl 1,4^ihydro-4-(2'-etiioxy-6'-pentadecylphenyl)-2-methyl-6-(5"-methyl-2-inercapto-
1 'H-benzimidazolyl)methyl-3,5-pyridine dicarboxylate;
dimethyl 1,4-dihydro-4-(2,-ethoxy-6'-pentadecylphenyl)-2-methyl-6-{5"-methyl-2-
mercapto-1 'H-benzimidazolyl)methyl-3,5-pyridine dicarboxylate;
diisopropyH,4-dihydro^2'-ethoxy-6'-pentadecylphenyl)-2-methyl-6-(5"-methyl-2-
mercapto-1'H- benzimidazolyl)melhyl-3,5-pyridine dicarboxylate;
diethyl 1,4-dmydro4 mercapto-1 'H-benzimidazolyl)methyl-3,5-pyridine dicarboxylate;
dimethyl 1,4-dihydrp-4-(2 '-methoxy-6'-pentadecylphenyl)-2-methyl-6-(5"-methyl-2-
mercapto-1 'H-benzimidazolyl)methyl-3,5-pyridine dicarboxylate;
diisopropyl 1,4-dmydro^2'-methoxy-6'-pentadecylphenyl>2-methyl-6-(5"-methyl-2-
mercapto-1 'H-benzimidazolyl)methyl-3,5-pyridine dicarboxylate;
diethyl 1,4-dihydro-4-(2'-isopropoxy-6'-pentadecylphenyl)-2-methyl-6-(5"-metixyl-2-
mercapto-1 'H-benzimidazolyl)methyl-3,5-pyridine dicarboxylate;
methyl-2-mercaptcHrH-ben2amidazolyl)methyl-3,5-pyridine dicarboxylate; and
diisopropyl 1,4-dihydro-4-(2'-isopropoxy-6'-pentadecylphenyl)-2-methyl-6-methyl (5'-
methyl-2-mercapto-l 'H-benzimidazolyl)methyl-3,5-pyridine dicarboxylate.
[0059] The structures of some of the above compounds are shown in Table 1.
a) R11-R13 and R15-R18, are each independently selected from the group consisting of
hydrogen, halogen, perhaloalkyl, nitro, amino, a diazo salt, optionally substituted
lower alkyl, alkoxy, optionally substituted lower alkylene and optionally
substituted five-membered or optionally substituted six-membered heteroaryl ring
or optionally substituted six-membered aryl or heteroaryl ring, wherein
said lower alkyl and said lower alkylene moieties are each independently
and optionally substituted with one or more substituents selected from the
group consisting of halogen, perhaloalkyl, nitro, amino, hydroxy, alkoxy,
sulfhydryl, thioether, cyano, amido, ester, and
A is selected from the group consisting of oxygen, sulfur, sulfoxide,
sulfone, and -NH;
R22 is selected from the group consisting of hydrogen, hydroxy, alkoxy,
haloalkoxy, halogen, haloalkyl, perhaloalkyl, nitro, amino, and a diazo salt;
n is between 0-4; and
said ring moieties are each independently and optionally substituted with
one or more substituents selected from the group consisting of lower alkyl,
lower alkylene,
b) Rl9 is selected from me group consisting of hydrogen, alkyl, alkylene, and a five-
membered or six-membered heteroaryl ring or a six-membered aryl or heteroaryl
ring, optionally substituted with one or more substituents selected from the group
consisting of lower alkyl, lower alkylene, halogen, perhaloalkyl, nitro, amino,
cyano, amido, and ester; and
c) R20 is selected from the group consisting of hydrogen and lower alkyl
d) R21 is selected from the group consisting of:
i) hydrogen, alkyl, alkoxy, alkylene, and a five-membered or six-membered
heteroaryl ring or a six-membered aryl or heteroaryl ring, optionally
substituted with one or more substituents selected from the group
consisting of lower alkyl, lower alkylene, halogen, perhaloalkyl, nitro,
amino, cyano, amido, and ester;
ii) COY wherein Y is C1-C8 alkyl, C1-C8 alkoxy or NR13R14, wherein R13 is
hydrogen or C1-C8 alkyl and R14 is hydrogen, C1-C8 alkyl, or C1-C14
phenalkyl;
iii) X or COX wherein X is
iv) halogen, CF3, cyano, nitro, COONHR3J, COON(R35)2, COOSO2R38,
COONR35S02N(R35)2, CO2R35) COON(R3S)2, COOS02N(R35)2,
COOSO2R38.
v) CONR25R26, wherein R25 is selected from the group consisting of
hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl and R26 is selected from the
group consisting of hydrogen, alkyl, cycloalkyl, aryl, or halosubstituted
alkyl, or R25 and R26 taken together with the nitrogen atom to which they
are attached form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl,
4-thiamorpholinyl, 1-piperazinyl, 4-diarylalkyl-l-piperazinyl, each of
which is optionally substituted with one or more substituents selected from
the group consisting of alkyl, alkoxy, alkylthio, halo, trifloromethyl, or
hydroxy,
vi) Z, COOZ, or C(0)(NH)Z, wherein Z is selected from the group consisting
of
wherein
A) p and q are each independently 0-10;
B) R30 is phenyl optionally substituted with one or more substituents
independently selected from the group consisting of halogen, CF3,
cyano, nitro, N(R35)2, NR35CONR37, NR35CON(R37)2, NR35SO2R38,
NR35S02N(R37)2, (CH2)0-4mCO2R35, (CH2)wCON(R35)2, (CH2)o-
4S02N(R3J)2, (CH2)0-4mSO2R38, and C1-4 alkyl;
C) R31 is selected from the group consisting of hydrogen, cyano,
OR38, COOR35, CON(R35)2, and phenyl optionally substituted with
one or more substituents independently selected from the group
consisting of halogen, CF3, cyano, nitro, N(R35)2, NR35CONR37,
NR35CON(R37)2, NR35SO2R38, NR35SO2N(R37)2, (CH2)0-4mCO2R35,
(CH2)0-4CON(R35)2, (CH2)SO2N(R35)2, (CH2)0-4SO2R38, and C1-4
alkyl;
D) R35 and R37 are each independently selected from hydrogen, C1-8
alkyl, C3-8 cycloalkyl, (CH2)0-4CF3; and
E) R38 is selected from the group consisting of hydrogen, C1-8 alkyl,
C3-8 cycloalkyl, and (CH2)(mCF3;
e) X is oxygen or sulfur, and
f) Q is oxygen or nitrogen; provided that when Q is oxygen R13 does not exist.
[0061] In certain embodiments, R11 is hydrogen or optionally substituted lower alkyl.
In some of these embodiments, R11 is selected from the group consisting of methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, tert-butyl, and pentyl. Some embodiments include those in which R11
is methyl or ethyl.

where A is selected from fee group consisting of oxygen, sulfur, and -NH and R^ is selected from
fee group consisting of hydrogen, hydroxy, alkoxy, haloalkoxy, halogen, haloalkyl, perhaloalkyl,
nitro, amino, and a diazo salt, and n is between 0-4.
[0063] While in some embodiments A is oxygen, in other embodiments A is sulfur,
and in still other embodiments A is -NH. In certain embodiments R22 is hydrogen.
[0064] In some embodiments, RI2 and Rt3 are each independently hydrogen or lower
alkyl. In some of these embodiments, R12 and R13 may each be independently selected from the
group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and pentyl.
[0065] In certain embodiments, R,s is hydrogen or lower alkyl. In some of these
embodiments Ri5 may be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl,
n-butyl, sec-butyl, tert-butyl, and pentyl.
[0066] Embodiments of the present invention include compounds of Formula II, in
which R16-R18 are each independently hydrogen or lower alkyl. In some embodiments R19 is
hydrogen or alkyl. When R!9 is alkyl, it may be a straight chain alkyl or a branched alkyl. In either
case, R19 may comprise at least 30 carbon atoms, at least 20 carbon atoms, at least 15 carbon atoms,
or at least 10 carbon atoms. Thus, R19 may be a pentadecyl (Cl5H31) group, a dodecyl (C12H25)
group, or a decyl (CI0H21) group.
[0067] In some embodiments, R20 is hydrogen.
[0068] In certain embodiments, R21 may be selected from the group consisting of
hydrogen, alkyl, and alkoxy. When R21 is alkoxy, it may be selected from the group consisting of
methoxy, ethoxy, and propoxy.
[0069] In some embodiments, R21 is COY, where Y is as defined herein. In certain of
these embodiments Y is C1-C8 alkyoxy or NR13R14, where R23 is hydrogen or C1-C8 alkyl and R24 is
hydrogen, C1-C8 alkyl, or C1-Q4 phenalkyl. A "phenalkyl" group is one in which an optionally
substituted phenyl group is attached to an alkyl substituent Thus, C6H5-CH-2- is a C1 phenalkyl
group. The phenyl group may be substituted as set forth herein.
[0070] In certain embodiments, Y may be a C1-C4 alkyoxy, which may be an ethoxy.
In other embodiments Y may be NR23R24, where R23 and R24 may each be independently C1-C8
alkyl. In some of these embodiments R23 and R24 are each methyl.
[0071] In some embodiments, R21 is selected from the group consisting of
COONHR35, COON(R35)2, COOSO2R38, COONR35SO2N(R35)2, CO2R35, COON(R35)2,
COOSO2N(R35)2, and COOSO2R38.
[0072] In other embodiments, R21 is X or COX, as X is defined herein, while in still
other embodiments, R2) is Z, COOZ, or C(0)(NH)Z, as Z is defined herein. When R21 comprises
the X substituent, p may be 0-8, 0-5, 0-3, or 0-2. hi some embodiments p is 0, while in other
embodiments p is 2. When R2i comprises the Z substituent, p and q may each independently be 0-
8, 0-5, 0-3, or 0-2. In some embodiments p and q are each independently 0, while in other
embodiments p and q are each independently 2.
[0073] Whether R21 comprises the X substituent or the Z substituent, RM is phenyl
optionally substituted with one or more substituents independently selected from the group
consisting of halogen, CF3, cyano, nitro, H(R35)2, NR35CONR37, NR35CONCR37)2, NR35SO2R38,
NR35SO2N(37)2, (CH2)(mCO2R35, (CH2)0-4CON(R35)2, (CH2)0-4SO(R35)2 (CH^SO.R-.g, and CM
alkyl. In some embodiments the phenyl is unsubstituted, while in other embodiments it is
substituted. In certain of these embodiments, the phenyl is substituted with halogen, which may be
a fluorine. In other embodiments the phenyl is substituted with (CH2)0-4CO2R35. In some of these
latter embodiments, the phenyl may be substituted with -COOCH3.
[0074] In certain embodiments Q is nitrogen, hi some of these embodiments the
moiety -C(0)QRi2Ri3 may be -C(0)NH2. In other embodiments Q is oxygen, in which case it is
singly substituted and Rj3 does not exist.
[0075] Thus, some of the compounds of the above invention are listed in Table 2.
II. Combination Therapy
[0077] While each compound of the present invention may be administered as the sole
active ingredient in a pharmaceutical composition, the compounds of the present invention may be
combined with other active ingredients in order to cause a more pronounced affect in the individual
patient. Thus, in another aspect, the present invention relates to a pharmaceutical combination
comprising a compound of Formula I or n, as described above, and a second comnound.
[0078] In certain embodiments, the second compound may be an angiotensin
converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB). A number of
ACE inhibitors are commercially available. These compounds, whose chemical structure is
somewhat similar, include lisinopril, enalapril, quinapril, ramipril, benazepril, captopril, fosinopril,
moexipril, trandolapril, and perindopril. ACE inhibitors, generally, are compounds that inhibit the
action of angiotensin converting enzyme, which converts angiotensin I to angiotensin II. The scope
of the present invention includes all those_ACE inhibitors now known and all those ACE inhibitors
to be discovered in the future.
[0079[ A number of ARBs are also commercially available or known in the art These
compounds include losartan, irbesartan, candesartan, telmisartan, eposartan, and valsartan. ARBs
reduce blood pressure by relaxing blood vessels. This allows better blood flow. ARBs function
stems from their ability to block the binding of angiotensin n, which would normally cause vessels
to constrict. The scope of the present invention includes all those ARBs now known and all those
ARBs to be discovered in the future.
[0080] In other embodiments, the second compound in the pharmaceutical
compositions of the present invention may be a beta-blocker. A number of beta-blockers are
commercially available. These compounds include atenolol, metoprolol succinate, metoprolol
tartrate, propranolol hydrochloride,. nadolol, atenolol, acebutolol hydrochloride, bisoprolol
fumarate, nadolol, pindolol, bisoprolol fumarate, acebutolol hydrochloride, betaxolol
hydrochloride, penbutolol sulfate, timolol maleate, carteolol hydrochloride, esmolol hydrochloride,
and atenolol. Beta-blockers, generally, are betaj and/or beta2 adrenergic receptor blocking agents,
which decrease the positive chronotropic, positive inotropic, bronchodilator, and vasodilator
responses caused by beta-adrenergic receptor agonists. The scope of the present invention includes
all those beta-blockers now knosm and all those beta-blockers to be discovered in the future.
[0081] In another embodiment, the second compound is a cardiac (or digitalis)
glycoside, such as digoxin.
[0082] In another aspect, the present invention relates to a pharmaceutical
composition comprising a calcium channel blocker and a second compound. The calcium channel
blocker may be selected from the group consisting of amlodipine, bepridil, diltiazem, isradipine,
felqdipine, nribefradil, nicardipine, nifedipine, nimodipine, nisoldipine, and verapamil. The second
compound may be an ACE inhibitor, an ARB, or a beta-blocker, as described herein.
III. Methods of Treatment
[0083] In another aspect, the invention relates to a method of modulating the activity
of a calcium channel in a cell comprising the step of contacting said cell with a compound of
Formula I or n, as described above. The calcium channel being modulated may be a low voltage
activated calcium channel or a high voltage activated calcium channel.
[0084] In a further aspect, the invention relates to a method of treating a disease
associated with a cellular' calcium channel comprising identifying a subject in need of such
treatment, and administering to the subject a therapeutically effective amount of a compound of
Formula I or n, as described above. In certain embodiments, the subject may be a mammal. The
mammal may be selected from the group consisting of mice, rats, rabbits, guinea pigs, dogs, cats,
sheep, goats, cows, primates, such as monkeys, chimpanzees, and apes, and humans. In some
embodiments, the subject is a human.
[0085] Embodiments of the invention include those in which the disease to be treated
is a cardiovascular disease. Examples of cardiovascular disease include arteriosclerosis,
atherosclerosis, hypertension, unstable angina, cardiac arrythrnia, myocardial infarction, atrial
fibrillation, and stroke.
[0086] In other embodiments of the invention, the disease to be treated is migraine
headaches, Raynaud's phenomenon (a condition in which arteries in the extremities spasm, causing
pallor), menstrual cramps, spinal-cord injuries, kidney failure, cancer, or premature labor.
[0087] In another aspect, the invention relates to a method for inhibiting calcium T-
channel activity, comprising the steps of providing a selective T-channel antagonist having an onset
of activity in reducing systolic blood pressure in vivo of at least three hours and a 'duration of
activity in vivo of at least 24 hours, wherein onset of activity refers to the time from administration
to maximum reduction of systolic blood pressure, and duration of activity refers to the time from
administration until the maximum amount of systolic blood pressure reduction achieved
subsequently decreases by at least 20 percent, and administering the antagonist to a mammal in
regular doses no more often than once per day.
[0088] The term "onset of activity" refers to the time from the point of administration
of the T-channel antagonist to the point where maximum reduction of systolic blood pressure is
achieved. Following the period of onset of activity, the systolic blood pressure begins to rise, until
eventually, the final systolic pressure reaches the same level as it was prior to the administration of
the antagonist Thus, over time the amount of systolilc blood pressure reduction decreases, from
the maximum reduction, to 90% of the maximum reduction, to 80% of the maximum reduction,
etc., until to 20% of the maximum reduction, and then 10% of the maximum reduction. "Duration
of activity" refers to the time from administration until the amount of maximum systolic blood
pressure reduction achieved subsequently decreases by at least 20 percent.
[0089] In certain embodiments, the T-channel antagonist has a cyclic ring structure
with a pendent alkylene group of at least 6 carbon atoms, hi other embodiments, the T-channel
antagonist is a compound of Formula I or U, described in Section I above:

where R1-R21 are as defined herein.
[0090] In certain embodiment, the T-channel antagonist is a prodrug.
[0091] In another aspect, the invention relates to a method for treating hypertension,
comprising repeatedly administering to a patient a selective T-channel antagonist in individual
dosages spaced at least one day apart
[0092] In a further aspect, the invention relates to a method for selecting calcium T-
channel antagonists having a desired pharmacological profile, comprising testing candidate
compounds to measure rapidity of onset of activity; testing candidate compounds to measure
duration of activity; and selecting candidate compounds having a slower onset of activity and a
longer duration of activity than Mibefradil.
[0093] hi some embodiments, at least one of the testing steps is performed in vitro;
whereas in other embodiments at least one of the testing steps is performed in vivo.
[0094] Thus, any compound that is a selective T-channel antagonist, having a slower
onset of activity and a longer duration of activity man Mibefradil is within the contemplation and
scope of the claims of the present invention. The onset of activity and the duration of activity can
be measured by the assays described herein. Thus, in one aspect, the present invention relates to
identifying a compound as a T-channel antagonist, determining its onset of activity and duration of
acitvity by the methods described herein, compare those results with data known for Mibefradil,
and determining that the compound has a slower onset of activity and a longer duration of activity
than Mibefradil.
[0095] Several compounds have been tested in connection with the present invention.
These tests demonstrate the relatively slow time course of block that can be accomplished with
judicious selection of the administered compound.
[0096] Specifically, individual HEK cells were tested in vitro using a patch-clamp
assay for T-channel blockage. Tests were performed at concentrations of 500 nM and luM, and
the time course of the blockage was followed for a period of several minutes.
[0097] In the past, patch clamp assays for T-channel activity would measure inhibition
of calcium-ion-mediated current over the course of only a few minutes, e.g., 2, 3, or 5 minutes. We
have discovered that there are a number of active T-channel blockers that exhibit a surprisingly
slow onset of activity, and a long time course of activity. The assays described herein can be used
to differentiate between conventional-type T-channel blockers, which usually show a time constant
of blockage of a few seconds, and the long-acting T-channel blockers, which show time constants
between 1 minute and 2, 4, 5, 10 or more minutes. It is the latter group of compounds that is
particularly interesting and useful in the present invention.
[0098] One conventional T-channel blocker, Mibefradil, exhibits a time constant of
blockage of about 12 seconds. This time constant is described as one-third of the time required to
achieve a complete blockage of current; hi contrast, compounds of the present invention
demonstrated a much slower time course of blockage. Preliminary numbers, which are subject to
refinement with further studies, show the following:

[0099] Thus, each of the compounds exhibits a time constant of at least one minute,
indicating extremely slow onset as compared to Mibefradil, with a time constant of 12 seconds.
However, in each case, the ED50 (defined as the dosage required to achieve a 50% blockage of T-
channel current) was between about 25 nM and about 1000 nM.
[0100] In addition to the referenced in vitro studies, in vivo studies have also been
conducted. The in vivo hypertension model used here involves administration of compound to
spontaneously hypertensive rats through IV tail injection of compound. Systolic blood pressure is
then measured using a tail cuff.
[0101] hi this study, as shown in Figure 1, PPK5 was adminstered in both a single
dose study and a multiple dose study. The results of the single dose study (20mg/Kg) showed that
systolic pressure dropped by about 48 mmHg in the first 5 hours, and dropped by about 55 mmHg
in the first 10 hours, after which it remained at that level past 24 hours. In comparison, the known
commercial T-channel blocker Mibefradil demonstrates a more volatile profile. When Mibefradil
is administered (30mg/Kg oral), systolic blood pressure spikes down by about 85 mmHg in the first
5 hours, and then recovers slowly for the next 5 hours and then more rapidly, so that by the end of
24 hours, systolic blood pressure has recovered by about 45 mmHg. (Based on data from NDA for
Mibefradil.)
[0102] Figure 2 references a multiple dose study in the spontaneously hypertensive
rat. Thus study utilizes three injections of PPK5, spaced about 25 hours apart. A relatively slow
onset is seen, with blood pressure dropping by about 55 mmHg, then remaining stable until the
second injection, after which it drops by about an additional 12 mmHg, where it remains through
the third injection until the end of the study. In contrast, 30 mg/Kg oral Miberfradil results in a
rapid drop of 85 mmHg, followed by more than 50% recovery within 24 hours of administration.
This demonstrates that a stable reduction of systolic pressure can readily be achieved using a
compound of the'present invention with a single daily dose, but that a conventional T-channel
blocker that shows a much more rapid onset in in vitro studies is unsuitable for adniimstration only
once a day.
PV. Pharmaceutical Compositions
[0103] hi another aspect, the invention relates to a pharmaceutical composition
comprising a compound of Formula I or n, as described above, and a physiologically acceptable
carrier, diluent, or excipient, or a combination thereof.
[0104] The term "pharmaceutical composition" refers to a mixture of a compound of
the invention with other chemical components, such as diluents or carriers. The pharmaceutical
composition facilitates administration of the compound to an organism. Multiple techniques of
administering a compound exist in the art including, but not limited to, oral, injection, aerosol,
parenteral, and topical administration. Pharmaceutical compositions can also be obtained by
reacting compounds with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric
acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic
acid, salicylic acid and the like.
[0105] The term "carrier" defines a chemical compound that facilitates the
incorporation of a compound into cells or tissues. For example dimethyl sulfoxide (DMSO) is a
commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or
tissues of an organism.
[0106] The term "diluent" defines chemical compounds diluted in water that will
dissolve the compound of interest as well as stabilize the biologically active form of the compound.
Salts dissolved in buffered solutions are utilized as diluents in the art. One commonly used
buffered solution is phosphate buffered saline because it mimics the salt conditions of human
blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent
rarely modifies the biological activity of a compound.
[0107] The term "physiologically acceptable" defines a carrier or diluent that does not
abrogate the biological activity and properties of the compound.
[0108] The compounds described herein can be administered to a human patient per
se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in
combination therapy, or suitable carriers or excipient(s). Techniques for formulation and
administration of the compounds of the instant application may be found in "Remington's
Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.
a) Routes Of Administration
[0109] Suitable routes of administration may, for example, include oral, rectal,
transmucosal, or intestinal administration; parenteral delivery, including intramuscular,
subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular,
intraperitoneal, intranasal, or intraocular injections.
[0110] Alternately, one may administer the compound in a local rather than systemic
manner, for example, via injection of the compound directly into a solid tumor, often in a depot or
sustained release formulation. Furthermore, one may administer the drug m a targeted drug
delivery system, for example, in a liposome coated with tumor-specific antibody. The liposomes
will be targeted to and taken up selectively by the tumor.
b) Composition/Formulation
[0111] The pharmaceutical compositions of the present invention may be
manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving,
granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabeleting
processes.
[0112] Pharmaceutical compositions for use in accordance with the present invention
thus may be formulated in conventional manner using one or more physiologically acceptable
carriers comprising excipients and auxiliaries which facilitate processing of the active compounds
into preparations which can be used pharmaceutically. Proper formulation is dependent upon the
route of administration chosen. Any of the well-known techniques, carriers, and excipients may be
used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.
[0113] For injection, the agents of the invention may be formulated in aqueous
solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's
solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to
the barrier to be permeated are used in the formulation. Such penetrants are generally known in the
art.
[0114] For oral administration, the compounds., can be formulated readily by
combining the active compounds with pharmaceutically acceptable carriers well known in the art
Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees,
capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to
be treated. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid
excipient with one or more compound of the invention, optionally grinding the resulting mixture,
and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets
or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose,
sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat
starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose,
hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone
(PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
[0115] Dragee cores are provided with suitable coatings. For this purpose,
concentrated sugar solutions may be used, which may optionally contain gum arabic, talc,
polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added
to the tablets or dragee coatings for identification or to characterize different combinations of
active compound doses.
[0116] Pharmaceutical preparations which can be used orally include push-fit capsules
made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol
or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as
lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in
suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. All formulations for oral administration should be in dosages suitable for
such administration.
[0117] For buccal administration, the compositions may take the form of tablets or
lozenges formulated in conventional manner.
[0118] For administration by inhalation, the compounds for use according to the
present invention are conveniently delivered in the form of an aerosol spray presentation from
pressurized packs or a nebuliser, with the use of a suitable propellant, e.g.,
dichlorodifiuoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or
other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by
providing a valve to deliver a metered amount Capsules and cartridges of, e.g., gelatin for use in
an inhaler or insufflator may be formulated containing a powder mix of the compound and a
suitable powder base such as lactose or starch.
[0119] The compounds may be formulated for parenteral administration by injection,
e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit
dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The
compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous
vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing
agents.
[0120] Pharmaceutical formulations for parenteral administration include aqueous
solutions of the active compounds in water-soluble form. Additionally, suspensions of the active
compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents
or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate
or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which
increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or
dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase
the solubility of the compounds to allow for the preparation of highly concentrated solutions.
[0121] Alternatively, the active ingredient may be in powder form for constitution
with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
[0122] The compounds may also be formulated in rectal compositions such as
suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa
butter or other glycerides.
[0123] In addition to the formulations described previously, the compounds may also
be formulated as a depot preparation. Such long acting formulations may be administered by
implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus,
for example, the compounds may be formulated with suitable polymeric or hydrophobic materials
(for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble
derivatives, for example, as a sparingly soluble salt
[0124] A pharmaceutical carrier for the hydrophobic compounds of the invention is a
cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic
polymer, and an aqueous phase. The cosolvent system may be the VPD co-solvent system. VPD is
a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™ , and
65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent
system (VPD:D5W) consists of VPD diluted 1:1 with a 5% dextrose in water solution. This
co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon
systemic administration. Naturally, the proportions of a co-solvent system may be varied
considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity
of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants
may be used instead of POLYSORBATE 80™; the fraction size of polyethylene glycol may be
varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone;
and other sugars or polysaccharides may substitute for dextrose.
[0125] Alternatively, other delivery systems for hydrophobic pharmaceutical
compounds may be employed. Liposomes and emulsions are well known examples of delivery
vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also
may be employed, although usually at the cost of greater toxicity. Additionally, the compounds
may be delivered using a sustained-release system, such as semipermeable matrices of solid
hydrophobic polymers containing the therapeutic agent Various sustained-release materials have
been established and are well known by those skilled in the art Sustained-release capsules may,
depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
Depending on the chemical nature and the biological stability of the therapeutic reagent, additional
strategies for protein stabilization maybe employed.
[0126] Many of the compounds of the invention may be provided as salts with
pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with
many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic,
succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the
corresponding free acid or base forms.
cY Effective Dosage.
[0127] Pharmaceutical compositions suitable for use in the present invention include
compositions where the active ingredients are contained in an amount effective to achieve its
intended purpose. More specifically, a therapeutically effective amount means an amount of
compound effective to prevent alleviate or ameliorate symptoms of disease or prolong the survival
of the subject being treated. Determination of a therapeutically effective amount is well within the
capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
[0128] For any compound used in the methods of the invention, the therapeutically
effective dose can be estimated initially from cell culture assays. For example, a dose can be
formulated in animal models to achieve a circulating concentration range that includes the IQo as
determined in cell culture. Such information can be used to more accurately determine useful
doses in humans.
[0129] Toxicity and therapeutic efficacy of the compounds described herein can be
determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g.,
for determining the LD50 (the dose lethal to 50% of the population) and the EDso (the dose
therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic
effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED5o-
Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell
culture assays and animal studies can be used in formulating a range of dosage for use in human.
The dosage of such compounds lies preferably within a range of circulating concentrations that
include the ED50 with little or no toxicity. The dosage may vary within this range depending upon
the dosage form employed and the route of administration utilized. The exact formulation, route of
administration and dosage can be chosen by the individual physician in view of the patient's
condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p.
1). Typically, the dose range of the composition administered to the patient can be from about 0.5
to 1000 mg/kg of the patient's body weight The dosage may be a single one or a series of two or
more given in the course of one or more days, as is needed by the patient.
[0130] The daily dosage regimen for an adult human patient may be, for example, an
oral dose of between 0.1 mg and 500 mg, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or
an intravenous, subcutaneous, or intramuscular dose of between 0.01 mg and 100 mg, preferably
between 0.1 mg and 60 mg, e.g. 1 to 40 mg of the compound of the formula (I) or a
pharmaceutically acceptable salt thereof calculated as the free base, the compound being
administered 1 to 4 times per day. Alternatively the compounds of the invention may be
administered by continuous intravenous infusion, preferably at a dose of up to 400 mg per day.
Thus, the total daily dosage by oral administration will be in the range 1 to 2000 mg and the total
daily dosage by parenteral administration will be in the range 0.1 to 400 mg. Suitably the
compounds will be administered for a period of continuous therapy, for example for a week or
more.
[0131] Dosage amount and interval may be adjusted individually to provide plasma
levels of the active moiety which are sufficient to maintain the modulating effects, or minimal
effective concentration (MEC). The MEC will vary for each compound but can be estimated from
in vitro data; e.g., the concentration necessary to achieve 50-90% of calcium channel blockage,
using the assays known in the art Dosages necessary to achieve the MEC will depend on
individual characteristics and route of administration. However, HPLC assays or bioassays can be
used to determine plasma concentrations.
[0132] Dosage intervals can also be determined using MEC value. Compounds
should be administered using a regimen which maintains plasma levels above the MEC for 10-90%
of the time, preferably between 30-90% and most preferably between 50-90%.
[0133] In cases of local administration or selective uptake, the effective local
concentration of the drug may not be related to plasma concentration.
[0134] The amount of composition administered will, of course, be dependent on the
subject being treated, on the subject's weight, the severity of the affliction, the manner of
administration and the judgment of the prescribing physician.
d) Packaging
[0135] The compositions may, if desired, be presented in a pack or dispenser device
which may contain one or more unit dosage forms containing the active ingredient The pack may
for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device
may be accompanied by instructions for administration. The pack or dispenser may also be
accompanied with a notice associated with the container in form prescribed by a governmental
agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of
approval by the agency of the form of the drug for human or veterinary administration. Such
notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for
prescription drugs, or the approved product insert Compositions comprising a compound of the
invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an
appropriate container, and labeled for treatment of an indicated condition.
V. Synthesis of the Compounds of Formula I
[0136] The compounds of the general Formula I were prepared by the well-known
Hantzsch dihydropyridine synthesis. In this method appropriate aldehyde was condensed with an
appropriate beta keto esters like methyl acetoacetate, ethyl acetoacetate, isopropyl acetoacetate,
ethyl 4-chloro acetoacetate and like, in inert solvent such as methanol, ethanol, isopropyl alcohol,
n-butanol, an ether solvent such as 1,2-dimethoxyethane or tetrahydrofuran (THF), an amide
solvent such as dimethyl formamide (DMF) or N-methylpyrrolidone, a sulfoxide solvent such as
dimethyl sulfoxide (DMSO) or sulfolane, an aromatic hydrocarbon solvent such as benzene,
toluene or xylene in presence of piperidine and acetic acid. If required, the knoevenegal product
was purified by column chromatography and reacted with appropriate amino crotonate like methyl-
3-amino crotonate, ethyl 3-amino crotonate, isopropyl 3-amino crotonate. The reaction is usually
conducted at temperature from room temperature to 200 °C, preferably from 60 to 140 °C, for from
1-100 hours, preferably from 6 to 40 hours. The corresponding Hantzsch product was purified by
column chromatography using silicagel (100-200 mesh) and/or crystallised using appropriate
organic solvents like hexane, petroleum ether (40-60 °C), ethanol etc. Substrates like 2-mercapto
benzimidazole, (5 -methyl)2-mercapto benzimidazole, 2-amino ethanol and like as mentioned in
claim 1 were used for substitutions on dihydropyridine ring.
[0137] For the processes mentioned above, any desired ratio of the substances
participating in the reaction can be used. In general, however, the process is carried out with molar
amounts of the reactants.
[0138] The synthesis of compounds includes enantiomerically pure forms obtained by
methods such as, by separating diastereomer mixtures of the compounds of the general Formula I,
from an enantiomerically pure chiral alcohol, by a customary method, subsequently preparing the
enantiomerically pure carboxylic acids and/or any methods used for separation of enantiomers, for
example, methods discussed by S. Goldmann and J. Stoltefuss [S. Goldmann and J. Stoltefuss "1,4-
Dihydropyridine: Effects of chirality and conformation on the calcium antagonist and calcium
agonist activities" Angewandte Chemie International Edition (English) 30,1559-1578 (1991)}.
[0139] As indicated above, the compounds and compositions of this invention are
useful as calcium entry blockers, and thus have broad pharmacological utility in that they exhibit
(i) pronounced and long-lasting vasodilating effect accompanied by an energy-sparing effect on
cardiac metabolism; (ii) antiarrythmic and antianginal action on cardiac muscle; (iii) vascular
spasmolytic action; (iv) antihypertensive action; (v) spasmolytic action on the smooth muscle of
the gastrointestinal and urogenital tracts and the cerebrovascular and respiratory systems; (vi) as
antihypercholestorolemic and antilipidemic agents; (vii) protection of the ischemic myocardium;
(viii) inhibit irritable bowel syndrome and esophagel spasm; (ix)inhibit migraine; and, (x) epilepsy.
Some of are also useful cardiotonic agents. This list also includes any cardiovascular problems
related to low voltaee activated (LVA) and high voltage activated (HVA) calcium channels.
[0140] The representative compounds of the present invention might inhibit vascular
calcium contraction, reduce cardiac contractile force, inhibit calcium mediated tracheal
contraction, inhibit calcium uptake in pituitary cells, or displace tritiated nitrendipine from
membrane.
VI. Synthesis of the Compounds of Formula II
[0141] The compounds of the present invention can be divided into two general
categories: those with a substitution at a nitrogen (either position 1 or position 3) of the pyrrolidine
ring and those without any substitution at that point, i.e., where that position is occupied by -NH.
Scheme 1, below, shows the synthetic procedure for synthesizing compounds without N-
substitution.
Examples
[0143] The examples below are illustrative of some of the embodiments of the
invention only and should not be construed to limit the scope of the claims.
Example 1: Extraction of ene mixture of anacardic acid (2-hydroxv-6-pentadecyl benzoic acid)
from solvent extracted CNSL
[0144] Commercially available solvent extracted cashew nut shell liquid (CNSL) (100
g) was dissolved in 5% aqueous methanol (600 mL). To the methanolic solution was added
activated charcoal (20 g), stirred for 15 minutes, then filtered over celite bed to remove any
insoluble material. The clear filtrate was transferred into three neck round bottom flask fitted with
a double surface reflux condenser and mechanical stirrer. Calcium hydroxide (50 g) was added in
portions at room temperature and the reaction mass temperature was raised to 50 °C and allowed to
maintain for 3 hrs. Progress of the reaction was monitored by thin layer chromatography (TLC)
using hexane-ethyl acetate (8:2) as mobile phase. After the completion of reaction, the precipitated
calcium anacardate was filtered and washed thoroughly with methanol (200 mL). The resultant
cake was dried under vacuum at 45-50 °C for 2 hrs to yield calcium anacardate (120 g).
[0145] Dry cake (120 g) was suspended in distilled water (440 mL), added
concentrated hydrochloric acid (33%, 60 mL) and stirred for 1 hr. Resultant solution was extracted
with ethylacetate (2 X 150 mL). The combined organic layer was washed with distilled water (2 X
500 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield an
ene mixture of anacardic acid. (Yield: 60 g).
Example 2: Hvdrogenation of anacardic acid ene mixture
[0146] Anacardic acid ene mixture (30 g,) was dissolved in methanol (120 ml). 5%
Pd/C (0.75 g, 2.5%) was added slowly and this solution were transferred to 250-mL hydrogenation
flask. Initially the solution was flushed with nitrogen and then with hydrogen. Hydrogenation was
carried out with 2.5 kg/cm2 hydrogen gas pressure for 2 hrs. Then the solution was filtered through
a celite bed to obtain catalyst free solution. This was evaporated under vacuum to get crude
saturated anacardic acid. It was then recrystallised from petroleum ether (Yield: 25 g).
Example 3: Synthesis of ethyl 2-ethoxv-6-pentadecvl- benzoate:
[0147] Anacardic acid (10.11 g, 29 mmol) was dissolved in acetone (60 mL) and
potassium carbonate ( 4.0 g, 29 mmol) was charged. Diethyl sulfate ( 8.93 g, 58 mmol) was added
slowly under stirring. This solution was then transferred to a three-neck flask fitted with a reflux
condenser and mechanical stirrer, and refluxed for 4 hrs. Progress of reaction was monitored by
TLC (mobile phase:Hexane:EtOAc 9:1). After completion of reaction, it was filtered and acetone
was evaporated under vacuum. Crude product was dissolved in dichloromethane (50 mL) and
washed with water (2 X 50 mL), 5% sodium bicarbonate solution (50 mL), saturated brine (50 mL)
and finally with distilled water (2 X 50 mL). The organic layer was dried over anhydrous sodium
sulphate, and evaporated under vacuum to give ethyl 2-ethoxy-6-pentadecyl- benzoate as oil. This
was then dissolved in minimum amount of petroleum ether (40-60 °C) and cooled to 0 °C to give
light brownish crystals (Yield: 12 g).
Example 4: Synthesis of isopropvl 2-isopropoxv-6-pentadecvl- benzoate:
[0148] Anacardic acid (10.11 g, 29 mmol) was dissolved in isobutyl methyl ketone
(60 mL), To this, finely powdered potassium carbonate (4.0 g, 29 mmol) and benzyl tributyl
ammonium chloride (1 g) was added. Slowly, isopropyl bromide (7.13 g, 58 mmol) was added and
refluxed for 8 hrs. TLC was checked in hexane:EtOAc (9:1). Solution was filtered and evaporated
under vacuum to give a viscous liquid. Crude product was dissolved in dichloromethane (50 mL)
and washed with water (2 X 50 mL), 5% sodium bicarbonate solution (50 mL), saturated brine (50
mL) and finally with water (2 X 50 mL). The organic layer was dried over anhydrous sodium
sulfate and evaporated under vacuum to givejsopropyl 2-isopropoxy-6-pentadecyl- benzoate as oil
(Yield: 12 g).
Example 5: Synthesis of 2-ethoxv-6-pentadecvl-benzyl alcohol:
[0149] Ethyl 2-ethoxy-6-pentadecyl-benzoate (10.9 g, 27 mmol) was dissolved in dry
tetrahydrofuran (60 mL). This solution was transferred to dry 250 mL three neck round bottom
flask fitted with reflux condenser, mechanical stirrer and it was maintained under nitrogen
atmosphere through out the reaction. To this lithium aluminum hydride (2.04 g, 54 mmol) was
added slowly. Reaction was highly exothermic. After addition the solution was slowly brought to
the reflux temperature and maintained at that temperature for about two hours and TLC was
checked in hexane:EtOAc (8:2). After completion of reaction, excess lithium aluminium hydride
was decomposed by drop-wise addition of ethylacetate (80 mL). To this 5 M HC1 (100 mL) was
added and organic layer was separated, dried over anhydrous sodium sulphate, concentrated under
vacuum to give a light brownish solid. This was recrystallised from petroleum ether (40-60 °C) to
give white solid. Yield: 8 g.
Example 6: Synthesis of 2-ethoxv-6-pentadecvl-benzaldehvde
[0150] To a 250 mL round bottom flask fitted with a reflux condenser, was added
pyridinium chloro chromate (PCC) (16.1 g, 75 mmol) in anhydrous dichloromethane (100 mL). 2-
Ethoxy-6-pentadecyl-benzyl alcohol (18.1 g, 50 mmol) in dichloromethane (10 mL) was added in
one portion to the magnetically stirred solution. After 1.5 hr dry ether (100 mL) was added and the
supernatant decanted from the black gum. The insoluble residue was washed thoroughly with
diethyl ether (3 X 25 mL), where upon it became black granular solid. The organic solution was
passed through a short pad of celite, and the solvent was removed by distillation to obtain brownish
low melting solid (Yield: 15 g).

[0151] 2-Ethoxy-6-pentadecyl benzaldehyde (3 g, 8.3 iranol) and ethyl acetoacetate
(1.08 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol) and
piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-amino
crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was evaporated
and reaction mixture was washed with distilled water and extracted with dichloromethane (10 mL).
Organic layer was dried over sodium sulfate, evaporated and compound was purified by column
chromatography using silicagel (100-200 mesh) with hexane.EtOAc (94:6) solvent system to give
diethyl 1,4-dihydro-4- (2,-ethoxy-6'-pentadecyl phenyl) -2,6-dimethyl-3,5- pyridine dicarboxylate
as white powder.

[0152] 2-Ethoxy-6-pentadecyl benzaldehyde (3 g, 8.3 mmol) and isopropyl
acetoacetate (1.19 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol)
and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-
amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was
evaporated and reaction mixture was washed with distilled water and extracted with
dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound
was purified by column chromatography using silica gel (100-200 mesh) with hexane:EtOAc (94:6)
solvent system to give ethyl isopropyl 1,4-dihydro-4- (2,-ethoxy-6'-pentadecylphenyl) -2,6-
dimethyl-3,5- pyridine dicarboxylate as viscous liquid .

10153] 2-Isopropoxy-6-pentadecyl benzaldehyde (3.1 g, 8.3 mmol) and methyl
acetoacetate (0.96 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol)
and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. methyl-3-
amino crotonate (0.97 g, 8.3 mmol) was then added and refluxed. for 10 hrs. n-Butanol was
evaporated and reaction mixture was washed with distilled water and extracted with
dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound
was purified by column chromatography using silicagel (100-200 mesh) with hexane:EtOAc (94:6)
solvent system to give dimethyl 1,4-dihydro-4-(2'-isopropoxy-6,-pentadecylphenyl)-2,6-dimethyl-
3,5-pyridine dicarboxylate as viscous liquid.

[0154] 2-Ethoxy-6-pentadecylbenzaldehyde (3 g, 8.3 mmol) and 4-chloro ethyl
acetoacetate (1.36 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol)
and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-
amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was
evaporated and reaction mixture was washed with distilled water and extracted with
dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound
was purified by column chromatography using silicagel (100-200 mesh) with hexane:EtOAc (94:6)
solvent system to give diethyl 1,4-dihydro-4-(2,-ethoxy-6'-pentadecylphenyl)-6-methyl-2-
chloromethyl-3,5-pyridme dicarboxylate. This compound (0.6 g, 1.2 mmol)was dissolved in
dichloromethane (10 mL) and then 2-mercapto-lH-benzimidazole (0.18 g, 1.2 mmol) and NaOH
(0.048 g, 1.2 mmol) were charged. Catalytic amount of tetrabutyl ammonium bromide was added
and magnetically stirred at room temperature for 2 hrs. The final compound was purified by
column chromatography as mentioned in Example 7.

[0155] 2-Ethoxy-6-pentadecyl benzaldehyde (3 g, 8.3 mmol) and methoxy ethyl
acetoacetate (1.32 g, 83 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol)
and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-
amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was
evaporated and reaction mixture was washed with distilled water and extracted with
dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound
was purified by column chromatography using silicagel (100-200 mesh) with hexane:EtOAc (94:6)
solvent system to give ethyl 2-methoxyemyl1,4-dmydro-4-(2,-ethoxy-6,--pentadecylphenyl)-2,6-
dimethyl-3,5 pyridine dicarboxylate.

[0156] 2-(2'-methoxyethoxy)-6-pentadecyl benzaldehyde (3.2 g, 8.3 mmol) and ethyl
acetoacetate (1.08 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol)
and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-
amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was
evaporated and reaction mixture was washed with distilled water and extracted with
dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound
was purified by column chromatography using silicagel (100-200 mesh) with hexane:EtOAc (94:6)
solvent system to give_diethyl 1,4-dihydro-4-(2'-(2"methoxy)ethoxy-6,-pentadecylphenyl)-2,6-
dimethyl-3,5-pyridine dicarboxylate.

[01571 2-Ethoxy-6-pentadecyl benzaldehyde (3 g, 8.3 mmol) and 4-chloro ethyl
acetoacetate (1.36 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol)
and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-
amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was
evaporated and reaction mixture was washed with distilled water and extracted with
dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound
was purified by column chromatography using silicagel (100-200 mesh) with hexanerEtOAc (94:6)
solvent system to give diethyl 1,4-dmydro-4^2'^tnoxy-6'-pentadecylphenyl)-2-chloromethyl-6-
mefhyl-3,5-pvridine dicarboxylate). This compound (0.6. g, 1 mmol )was dissolved in
dichlorornetbane (10 mL) and 2-amino ethanol (0.061 g, 1 mmol) and KOH (0.06 g, 1 mmol) were
added and stirred magnetically for 15 min. Then catalytic amount of dibenzo- 18-crown-6 and
tetrabutyl ammonium bromide was added and stirred for one hour. Then the product was purified
by column chromatography as mentioned in example 7.

[0158] 2-Ethoxy-3,5-dinitro-6-pentadecyl benzaldehyde (3.73 g, 8.3 mmol) and ethyl
acetoacetate (1.08 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol)
and piperidine (0.7 g, 83 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-
amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was
evaporated and reaction mixture was washed with distilled water and extracted with
dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound
was purified by column chromatography using silicagel (100-200 mesh) with hexane-.EtOAc (94:6)
solvent system to give diethyl 1,4-dihydro-4-(2'-ethoxy-3',5'-dinitro-6'-pentadecylphenyl)-2,6-
dimethyl-3,5-pyridine dicarboxylate.

(0159] 2-Efhoxy-3 -acetanilido-6i>entadecyl benzaldehyde (3.46 g, 8.3 mmol) and
ethyl acetoacetate (1.08 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3
mmol) and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs.
Ethyl-3-amino crotonate (1.08g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was
evaporated and reaction mixture was washed with distilled water and extracted with
dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound
was hydrolised and purified by column chromatography using silicagel (100-200 mesh) with
hexane:EtOAc (94:6) solvent system to give diethyl 1,4-dmyd^c-4-(2,-emoxy-3,-armno-6,-
pentadecyIphenyl)-2,6-dimemyl-3,5-pyridine.

10160] 2-Emoxy-6-pentadecyl benzaldehyde (3 g, 8.3 mmol) and 4-chloro ethyl
acetoacetate (1.36 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 83 mmol)
and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Bthyl-3-
amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was
evaporated and reaction mixture was washed with distilled water and extracted with
dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound
was purified by column chromatography using silicagel (100-200 mesh) with hexane:EtOAc (94:6)
solvent system to give diethyl 1,4-dihydro-4-(2'-ethoxy-6'-pentadecylphenyl)-6-memyl-2-
chloromethyl-3,5-pyridine dicarboxylate. This compound (0.6 g, 1 mmol) was dissolved in
dichloromethane (10 mL) and then (5'-methyl) 2-mercapto-lH-bezimidazole (0.164 g, 1 mmol) and
NaOH (0.04 g, 1 mmol) were charged. Catalytic amount of tetraburyl ammonium bromide and
dibenzo-18-crown-6 were added and magnetically stirred at room temperature for 2 hrs. The final
compound was purified by column chromatography as mentioned in Example 7.
Example 17: Synthesis of 1,4-dihvdro-2-rf(4-methoxvphenvl)methvnthio1-6-merhvl-4-r2-
memoxv-6-pentadecvlphenvl1-5-pvrimidinecarboxvlic acid ethyl ester.
{0161] The reaction mixture containing 2-[[2-methoxy-6-pentadecyl phenyl]
methylene]-3-oxobutanoic acid ethyl ester (3 g, 6.6 mmol), 2-((4-methoxyphenyl) memyl)-2-
thiopseudourea hydrochloride (1.2 g, 6.6 mmol), and sodium acetate (0.6 g, 7 mmol) in
dimethylformamide (30 mL) was heated at 70 °C for 4 h. The reaction was cooled to room
temperature, diluted with ether, and filtered. The filtrate was washed with water, sodium
bicarbonate, and brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and
the compound was obtained as brown viscous liquid.
Example 18: Synthesis of l^-dihvdro^-fr^methoxyphenvDmethvnoxvl-e-merhvM^-
methoxy-6-pentadecvlphenvn-S-pyrimidinecarboxvlic acid ethyl ester
[0162] The reaction mixture containing 2-[[2-methoxy-6-pentadecyl phenyl]
methylene]-3-oxobutanoic acid ethyl ester (3 g, 6.6 mmol), 2-((4-methoxyphenyl) memyl)-2-
oxypseudourea hydrochloride (1.1 g, 6.6. mmol), and sodium acetate (0.6 g, 7 mmol) in
dimethylformamide (30 mL) was heated at 70 °C for 4 h. The reaction was cooled to room
temperature, diluted with ether, and filtered. The filtrate was washed with water, sodium
bicarbonate, and brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and
the compound was obtained as brown viscous liquid.
Example 19: S-ethoxvcarbonvl-4-(2-ethoxv-6-Dentadecvlphenyl)-6-(2'-mercapto-rH-
benzimidazolyl) methyl-3,4-dihvdropyrimidin-2(lH)-one (PPK-21)
[0163] A solution of 4(2'-mercapto-rH-benzimidazoIyl) ethylacetoacetate (2.3 g, 8.3
mmol), 2-ethoxy-6-pentadecyl benzaldehyde (3 g, 8.3 mmol) and urea (1.0 g, 16.6 mmol) in
tetrahydrofuran (20 mL) was heated to reflux (65-70 °C) in the presence of hydrochloric acid
(30%) for 7 h. The reaction mixture after being cooled to room temperature was'poured into
crushed ice (20 g) and stirred for 5 min. The viscous liquid was extracted with ethylacetate (40 mL)
and was washed with IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over
anhydrous sodium sulfate, the solvent was evaporated to yield light yellow oil. This crude product
was purified by flash column chromatography and recrystallised from hexane to get white
crystalline solid of title compound.
[0164] Melting point : 87-88 °C
[0165] IR(cm-1) : 3425 (N-H), 2920 (C-H), 1694 (C=0)
[0166] Mass (Electrospray): 663 (M+l), 661 (M-l)
[0167] 'H NMR (8 ppm) : 8.5 (bs, 1H, D20 exchangeable, N-H) 7.7 (d, J=6 Hz, 1H,
Aromatic proton) 7.5 (m, 1H, Aromatic proton) 7.25 (m, 3H, Aromatic proton, N-H, D20
exchangeable) 7.15 (t, J=8 Hz, 1H, Aromatic proton) 6.85 (d, J=8Hz, 2H, Aromatic proton) 5.8 (s,
1H, C4-H) 4.6 (s, 1H, D2O exchangeable, N-H) 4.5 (s, 2H, S-CH2) 4.0 (m, J=6 Hz, 4H, 0-CH2) 3.1
(m, 1H, benzylic) 2.5 (m, 1H, benzylic) 1.85-1.1 (m, 35H, (CH2),3 from alkyl chain, CH3, CH3,
allylic CH3) 0.9 (dt, 3H, terminal CH3 from alkyl chain).

[0168] A solution of ethylacetoacetate (1.13 g, 8.6 mmol), 2-methoxy-6-pentadecyl
benzaldehyde (3 g, 8.6 mmol) and urea (1.04 g, 17.3 mmol) in tetrahydrofuran (20 mL) was heated
to reflux (65-70 °C) in the presence of hydrochloric acid (30%) for 7 h. The reaction mixture after
being cooled to room temperature was poured into crushed ice (20 g) and stirred for 5 min. The
viscous liquid was extracted with ethylacetate (40 mL) and was washed with IN hydrochloric acid,
water, sodium bicarbonate and brine. After drying over anhydrous sodium sulfate, the solvent was
evaporated to yield light yellow oil. This crude product was purified by flash column
chromatography and recrystallised from hexane to get white crystalline solid of title compound.
[0169] Melting point : 91-93 °C
[0170] IR(cm-1) : 3420 (N-H), 2922 (C-H), 1690 (C=O)
[0171] Mass (Electrospray): 501 (M+l), 499 (M-l)
[0172] 'H NMR (5 ppm) : 7.6 (bs, 1H, D2O exchangeable, N-H) 7.15 (t, J=8 Hz,
1H, aromatic proton) 6.85 (d, J=8Hz, 2H, aromatic protons) 5.95 (s, 1H, C4-H) 4.95 (s, 1H, D2O
exchangeable, N-H) 4.0 (m, 2H, O-CH2) 3.8 (s, 3H, O-CH3) 3.15 (m, 1H, benzylic) 2.5 (m, 1H,
benzylic) 2.25 (s, 3H, allylic) 1.85-0.95 (m, 29H, (CH2)13 from alkyl chain, CH3) 0.9 (dt, 3H,
terminal CH3 from alkyl chain).
[0173] bs-broad singlet, t-triplet, d-doublet, s-singlet, m-multiplet, dt-distorted triplet.
[0174] A solution of methylacetoacetate (1.2 g, 8.5 mmol), 2-ethoxy-6-pentadecyl
berizaldehyde (3 g, 8.5 mmol) and urea (1.00 g, 17 mmol) in tetrahydrofuran (20 mL) was heated to
reflux (65-70 °C) in the presence of hydrochloric acid (30%) for 7 h. The reaction mixture after
being cooled to room temperature was poured into crushed ice (20 g) and stirred for 5 min. The
viscous liquid was extracted with ethylacetate (40 mL) and was washed with IN hydrochloric acid,
water, sodium bicarbonate and brine. After drying over anhydrous sodium sulfate, the solvent was
evaporated to yield light yellow oil. This crude product was purified by flash column
chromatography and recrystallized from hexane to get white crystalline solid of title compound.
[0175] Melting point : 127-129 °C
[0176] IR (cm1) : 3426 (N-H), 2920 (C-H), 1694 (C=0)
[0177] Mass (Electrospray): 501 (M+l), 499 (M-l)
[0178] 'H NMR (8 ppm) : 7.6 (bs, 1H, D20 exchangeable, N-H) 7.1 (t, J=8 Hz, 1H,
aromatic proton) 6.72 (d, J=8Hz, 2H, aromatic protons) 5.8 (s, 1H, C4-H) 4.8 (s, 1H, D20
exchangeable, N-H) 4.0 (q, 2H, 1=6 Hz, 0-CH2) 3.5 (s, 3H, 0-CH3) 3.1 (m, 1H, benzylic) 2.5 (m,
1H, benzylic) 2.3 (s, 3H, allylic) 1.8-1.1 (m, 29H, (CH2)13 from alkyl chain, CH3) 0.85 (dt, 3H,
terminal CH3 from alkyl chain).
[0179] bs-broad singlet, t-triplet, d-doublet, s-singlet, m-multiplet, dt-distorted triplet,
q-rquartet

[0180] A solution of methylacetoacetate (1.2 g, 8.5 mmol), 2-methoxy-6-pentadecyl
benzaldehyde (3.1 g, 8.5 mmol) and urea (1.00 g, 17 mmol) in tetrahydrofuran (20 mL) was heated
to reflux (65-70 °C) in the presence of hydrochloric acid (30%) for 7 h. The reaction mixture after
being cooled to room temperature was poured into crushed ice (20 g) and stirred for 5 min. The
viscous liquid was extracted with ethylacetate (40 mL) and was washed with IN hydrochloric acid,
water, sodium bicarbonate and brine. After drying over anhydrous sodium sulfate, the solvent was
evaporated to yield light yellow oil. This crude product was purified by flash column
chromatography and recrystallized from hexane to get white crystalline solid of title compound.
[0181] Melting point : 101-102 °C
[0182] IR (cm"1) : 3425 (N-H), 2918 (C-H), 1690 (C=O)
[0183J Mass (Electrospray): 487 (M+l), 485 (M-l)
[0184] ,HNMR(8 ppm) : 7.6 (bs, 1H, D2O exchangeable, N-H) 7.15 (t, J=8 Hz,
1H, aromatic proton) 6.73 (d, J=8Hz, 2H, aromatic protons) 5.8 (s, 1H, C4-H) 4.8 (s, 1H, D2O
exchangeable, N-H) 3.78 (s, 3H, O-CH2) 3.6 (s, 3H, O-CH3) 3.1 (m, 1H, benzylic) 2.5 (m, 1H,
benzyUc) 2.3 (s, 3H, allylic) 1.8-1.1 (m, 26H, (CH2)13 from alkyl chain) 0.85 (dt, 3H, terminal CH3
from alkyl chain).
[0185] bs-broad singlet, t-triplet, d-doublet, s-singlet, m-multiplet, dt-distorted triplet,
q-quartet.

[0186] A solution of ethylacetoacetate (1.25 g, 8.5 mmol), 2-ethoxy-6-pentadecyl
benzaldehyde (3 g, 8.5 mmol) and urea (1.1 g, 17 mmol) in tetrahydrofuran (20 mL) was heated to
reflux (65-70 °C) in the presence of hydrochloric acid (30%) for 7 h. The reaction mixture after
being cooled to room temperature was poured into crushed ice (20 g) and stirred for 5 min. The
viscous liquid was extracted with ethylacetate (40 mL) and was washed with IN hydrochloric acid,
water, sodium bicarbonate and brine. After drying over anhydrous sodium sulfate, the solvent was
evaporated to yield light yellow oil. This crude product was purified by flash column
chromatography and recrystallized from hexane to get white crystalline solid of title compound.
[0187] Melting point : 99-100 °C
[0188] IR (cm1) : 3420 (N-H), 2924 (C-H), 1690 (CO)
[0189] Mass (Electrospray): 515 (M+l), 513 (M-l)
[0190] 1HNMR (5ppm) : 7.35 (bs, 1H, D2O exchangeable, N-H) 7.15 (t, J=8 Hz,
1H, aromatic proton) 6.72 (d, J=8Hz, 2H, aromatic protons) 5.8 (s, 1H, Q-H) 4.75 (s, 1H, D2O
exchangeable, N-H) 4.0 (m, 4H, O-CH2) 3.15 (m, 1H, benzylic) 2.45 (m, 1H, benzylic) 2.3 (s, 3H,
allylic) 1.8-1.1 (m, 32H, (CH2),3 from alkyl chain, CH3, CH3) 0.9 (dt, 3H, terminal CH3 from alkyl
chain).
[0191] bs-broad singlet, t-triplet, d-doublet, s-singlet, m-multiplet, dt-distorted triplet
Example 24: 5-methoxvcarbonvl-4-(2-rnethoxv-6-(8' Z, 11' Z. 14' Z) pentadecatrienvl phenvl)-6-
memvl-3.4-dihvdropyrimidin-2aHyonea>PK-26A)
[0192] A solution of methylacetoacetate (1.2 g, 8.5 mmol), 2-methoxy-6-(8' Z, 11' Z,
14' Z) pentadecatrienyl benzaldehyde (3.1 g, 8.5 mmol) and urea (1.00 g, 17 mmol) in
tetrahydrofuran (20 mL) was heated to reflux (65-70 °C) in the presence of hydrochloric acid
(30%) for 7 h. The reaction mixture after being cooled to room temperature was poured into
crushed ice (20 g) and stirred for 5 mm. The viscous liquid was extracted with ethylacetate (40 mL)
and was washed with IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over
anhydrous sodium sulfate, the solvent was evaporated to yield light yellow oil. This crude product
was purified by flash column chromatography and recrystallised from hexane to get white
crystalline solid of title compound.
[0193] IR (cm"1) : 3427 (N-H), 2922 (C-H), 1691 (C=0)
[0194] Mass (Electrospray): 481 (M+l), 479 (M-l)
Example 25: S-methoxvcarbonvl-4-(2-methoxv-6-(8' Z. 11' Z) pentadecadienvl phenvD-6-
methvl-3.4-dmvdropyrimidin-2flH)-one (PPK-26B0
[0195] A solution of methylacetoacetate (1.2 g, 8.5 mmol), 2-methoxy-6-(8' Z, 11' Z)
pentadecadienvl benzaldehyde(3.1 g, 8.5 mmol) and urea (1.00 g, 17 mmol) in tetrahydrofuran (20
mL) was heated to reflux (65-70 °C) in the presence of hydrochloric acid (30%) for 7 h. The
reaction mixture after being cooled to room temperature was poured into crushed ice (20 g) and
stirred for 5 min. The viscous liquid was extracted with ethylacetate (40 mL) and was washed with
IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over anhydrous sodium
sulfate, the solvent was evaporated to yield light yellow oil. This crude product was purified by
flash column chromatography.
[0196] IR (cm"1) : 3426 (N-H), 2920 (C-H), 1690 (CO)
[0197] Mass (Electrospray): 483 (M+l), 481 (M-l)
Example 26: 5-methoxvcarbonvl-4-(2-methoxv-6-f8' Z) pentadecenyl phenvI)-6-methvl-3.4-
dihvdropvrimidin-2(1H)-one (PPK-26C)
[0198] A solution of methylacetoacetate (1.2 g, 8.5 mmol), 2-methoxy-6-(8' Z)
pentadecenyl benzaldehyde (3.1 g, 8.5 mmol) and urea (1.00 g, 17 mmol) in tetrahydrofuran (20
mL) was heated to reflux (65-70 °C) in the presence hydrochloric acid (30%) for 7 h. The reaction
mixture after being cooled to room temperature was poured into crushed ice (20 g) and stirred for 5
min. The viscous liquid was extracted with ethylacetate (40 mL) and was washed with 1N
hydrochloric acid, water, sodium bicarbonate and brine. After drying over anhydrous sodium
sulfate, the solvent was evaporated to yield light yellow oil. This crude product was purified by
flash column chromatography.
[0199] IR (cm-1) : 3424 (N-H), 2924 (C-H), 1692 (C=O)
[0200] Mass (Electrospray): 485 (M+1), 483 (M-1)

[0201] A solution of ethylacetoacetate (1.3 g, 8.5 mmol), 2-ethoxy-6-(8' Z, 11' Z, 14'
Z) pentadecatrienyl benzaldehyde (3.2 g, 8.5 mmol) and urea (1.1 g, 17 mmol) in tetrahydrofuran
(20 mL) was heated to reflux (65-70 °C) in the presence of hydrochloric acid (30%) for 7 h. The
reaction mixture after being cooled to room temperature was poured into crushed ice (20 g) and
stirred for 5 min. The viscous liquid was extracted with ethylacetate (40 mL) and was washed with
IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over anhydrous sodium •
sulfate, the solvent was evaporated to yield light yellow oil. This crude product was purified by
flash column chromatography and recrystallised from hexane to get white crystalline solid of title
compound.
[0202] IR (cm1) : 3422 (N-H), 2920 (C-H), 1690 (C=O)
[0203] Mass (Electrospray): 509 (M+1), 507 (M-1)

10204] A solution of ethylacetoacetate (1.3 g, 8.5 mmol), 2-ethoxy-6-(8' Z, 11' Z)
pentadecadienyl benzaldehyde (3.2 g, 8.5 mmol) and urea (1.1 g, 17 mmol) in tetrahydrofuran (20
mL) was heated to reflux (65-70 °C) in the presence of hydrochloric acid (30%) for 7 h. The
reaction mixture after being cooled to room temperature was poured into crushed ice (20 g) and
stirred for 5 min. The viscous liquid was extracted with ethylacetate (40 mL) and was washed with
IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over anhydrous sodium
sulfate, the solvent was evaporated to yield light yellow oil. This crude product was purified by
flash column chromatography.
[0205] IR (cm-1) : 3424 (N-H), 2924 (C-H), 1691 (C=O)
[0206] Mass (Electrospray): 511 (M+1), 509 (M-1)

[0207] A solution of ethylacetoacetate (1.3 g, 8.5 mmol), 2-ethoxy-6-(8' Z)
pentadecenyl benzaldehyde (3.2 g, 8.5 mmol) and urea (1.1 g, 17 mmol) in tetrahydrofuran (20 mL)
was heated to reflux (65-70 °C in the presence of hydrochloric acid (30%) for 7 h. The reaction
mixture after being cooled to room temperature was poured into crushed ice (20 g) and stirred for 5
min. The viscous liquid was extracted with ethylacetate (40 mL) and was washed with IN
hydrochloric acid, water, sodium bicarbonate and brine. After drying over anhydrous sodium
sulfate, the solvent was evaporated to yield light yellow oil. This crude product was purified by
flash column chromatography.
[0208] IR (cm1) : 3423 (N-H), 2923 (C-H), 1691 (C=O)
[0209] Mass (Electrospray): 513 (M+1), 511 (M-1)

[0210] A solution of methylacetoacetate (1.2 g, 8.5 mmol), 2-ethoxy-6-(8' Z, 11' Z, 14'
Z) pentadecatrienyl benzaldehyde (3.2 g, 8.5 mmol) and urea (1.1 g, 17 mmol) in tetrahydrofuran
(20 mL) was heated to reflux (65-70 °C) in the presence of hydrochloric acid (30%) for 7 h. The
reaction mixture after being cooled to room temperature was poured into crushed ice (20 g) and
stirred for 5 min. The viscous liquid was extracted with ethylacetate (40 mL) and was washed with
IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over anhydrous sodium
sulfate, the solvent was evaporated to yield light yellow oil. This crude product was purified by
flash column chromatography and recrystallised from hexane to get white crystalline solid of title
compound.

[0213] A solution of methylacetoacetate (1.2 g, 8.5 mmol), 2-ethoxy-6-(8, Z, 11' Z)
pentadecadienyl benzaldehyde (3.2 g, 8.5 mmol) and urea (1.1 g, 17 mmol) in tetrahydrofuran (20
mL) was heated to reflux (65-70 °C) in the presence of hydrochloric acid (30%) for 7 h. The
reaction mixture after being cooled to room temperature was poured into crushed ice (20 g) and
stirred for 5 min. The viscous liquid was extracted with ethylacetate (40 mL) and was washed with
IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over anhydrous sodium
sulfate, the solvent was evaporated to yield light yellow oil. This crude product was purified by
flash column chromatography.
[0214J IR(cm-1) : 3423 (N-H), 2921 (C-H), 1690 (C=O)
[0215] Mass (Electrospray): 497 (M+1), 495 (M-1)

[0216] A solution of methylacetoacetate (1.2 g, 8.5 mmol), 2-ethoxy-6-(8' Z)
pentadecenyl benzaldehyde (32 g, 8.5 mmol) and urea (1.1 g, 17 mmol) in tetrahydrofuran (20 mL)
was heated to reflux (65-70 °C) in the presence of hydrochloric acid (30%) for 7 h. The reaction
mixture after being cooled to room temperature was poured into crushed ice (20 g) and stirred for 5
min. The viscous liquid was extracted with ethylacetate (40 mL) and was washed with IN
hydrochloric acid, water, sodium bicarbonate and brine. After drying over anhydrous sodium
sulfate, the solvent was evaporated to yield light yellow oil. This crude product was purified by
flash column chromatography.
[0217] IR (an-1) : 3422 (N-H), 2921 (C-H), 1691 (C=O)
[0218] Mass (Electrospray): 499 (M+1), 497 (M-1)

[0219] A solution of isopropylacetoacetate (1.3 g, 8.5 mmol), 2-ethoxy-6-(8' Z, 11' Z,
14' Z) pentadecatrienyl benzaldehyde (3.2 g, 8.5 mmol) and urea (1.1 g, 17 mmol) in
tetrahydrofuran (20 mL) was heated to reflux (65-70 °C) in the presence of hydrochloric acid
(30%) for 7 h. The reaction mixture after being cooled to room temperature was poured into
crushed ice (20 g) and stirred for 5 min. The viscous liquid was extracted with ethylacetate (40 mL)
and was washed with IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over
anhydrous sodium sulfate, the solvent was evaporated to yield light yellow oil. This crude product
was purified by flash column chromatography and recrystallised from hexane to get white
crystalline solid of title compound.

[0222J A solution of isopropylacetoacetate (1.3 g, 8.5 mmol), 2-ethoxy-6-(8' Z, 11' Z)
pentadecadienyl benzaldehyde (3.2 g, 8.5 mmol) and urea (1.1 g, 17 mmol) in tetrahydrofuran (20
mL) was heated to reflux (65-70 °C) in the presence of hydrochloric acid (30%) for 7 h. The
reaction mixture after being cooled to room temperature was poured into crushed ice (20 g) and
stirred for 5 min. The viscous liquid was extracted with ethylacetate (40 mL) and was washed with
IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over anhydrous sodium
sulfate, the solvent was evaporated to yield light yellow oil. This crude product was purified by
flash column chromatography.
[0223] IR (cm-1) : 3423 (N-H), 2921 (C-H), 1690 (CO)
[0224] Mass (Electrospray): 525 (M+1), 523 (M-1)

[0225] A solution of isopropylacetoacetate (1.3 g, 8.5 mmol), 2-ethoxy-6-(8' Z)
pentadecenyl benzaldehyde (3.2 g, 8.5 mmol) and urea (1.1 g, 17 mmol) in tetrahydrofuran (20 mL)
was heated to reflux (65-70 °C) in the presence of hydrochloric acid (30%) for 7 h. The reaction
mixture after being cooled to room temperature was poured into crushed ice (20 g) and stirred for 5
min. The viscous liquid was extracted with ethylacetate (40 mL) and was washed with IN
hydrochloric acid, water, sodium bicarbonate and brine. After drying over anhydrous sodium
sulfate, the solvent was evaporated to yield light yellow oil. This crude product was purified by
flash column chromatography.

[0228] The solution of 1,4-dihydro-2-[[(4-methoxyphenyl)methyl)oxy]-6-methyl-4-[2-
memoxy-6-pentadecylphenyl]-5-pyrimidinecarboxylic acid methyl ester (3 g, 4.6 mmol) in
dichloromethane (15 mL) and pyridine (1.5 mL) was treated with ethyl chloroformate (0.6 g, 4.7
mmol) at 0 °C under argon. After the addition was finished reaction was stirred at room
temperature for 12 h and then diluted with more dichloromethane. The resultant solution was
washed with IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over
anhydrous sodium sulfate, the solvent evaporated to yield light yellow oil. This crude product was
purified by flash column chromatography and recrystallised from hexane to get white crystalline
solid of title compound.
[0229] Melting point : 121 -122 °C
[0230] IR (an1) : 3340 (N-H), 2921 (C-H), 1696 (C=O)
[0231] Mass (Electrospray): 559 (M+1), 557 (M-1)
[0232] 'HNMR(8ppm) : 8.35 (bs, 1H, DjO exchangeable, N-H) 7.2 (t, J=8 Hz,
1H, aromatic proton) 6.85 (d, J=8Hz, 1H, aromatic proton) 6.7 (d, J=8Hz, 1H, aromatic proton)
6.55 (s, 1H, C6-H) 4.25 (q, 2H, J=6 Hz, 0-CH2) 3.75 (s, 3H, 0-CH3) 3.6 (s, 3H, 0-CH3) 3.1 (m, 1H,
benzylic) 3.0 (m, 1H, benzylic) 2.25 (s, 3H, allylic) 1.85-1.1 (m, 29H, (CH2),3 from alkyl chain,
CHj) 0.9 (dt, 3H, terminal CH3 from alkyl chain).
[0233] bs-broad singlet, t-triplet, d-doublet, s-singlet, m-multiplet, dt-distorted triplet
[0234] The solution of 1,4-dihydro-2-[[(4Hnethoxyphenyl)methyl)oxy]-6-methyl-4-[2-
memoxy-6-pentadecylphenyl]-5-pyrimidinecarboxylic acid ethyl ester (3 g, 4.7 mmol) in
dichloromethane (15 mL) and pyridine (1.5 mL) was treated with ethyl chloroformate (0.6 g, 4.7
mmol) at 0 °C under argon. After the addition was finished reaction was stirred at room
temperature for 12 h and then diluted with more dichloromethane. The resultant solution was
washed with IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over
anhydrous sodium sulfate, the solvent evaporated to yield light yellow oil. This crude product was
purified by flash column chromatography and recrystallised from hexane to get white crystalline
solid of title compound.
[0235] Melting point : 109-110 °C
[0236] IR (cm1) : 3348 (N-H), 2920 (C-H), 1697 (CO)
[0237] Mass (Electrospray): 573 (M+1), 571 (M-1)
[0238] 1HNMR(d ppm) : 8.1 (bs, 1H, D20 exchangeable, N-H) 7.15 (t, J=8 Hz,
1H, aromatic proton) 6.85 (d, J=8Hz, 1H, aromatic proton) 6.7 (d, J=8Hz, 1H, aromatic proton)
6.55 (s, 1H, C6-H) 4.1 (m, 4H, 0-CH2) 3.75 (s, 3H, 0-CH3) 3.1 (m, 1H, benzylic) 2.9 (m, 1H,
benzylic) 2.25 (s, 3H, allylic) 1:85-1.1 (m, 32H, (CH2)I3 from alkyl chain, CH3, CH3) 0.9 (dt, 3H,
terminal CH3 from alkyl chain).

[0240] The solution of 1,4-dihydro-2-[[(4-methoxyphenyl)methyl)oxy]-6-methyl-4-[2-
memoxy^-pentadecylphenyl]-5-pyrirnidinecarboxylic acid isopropyl ester (3 g, 4.8 mmol) in
dichloromethane (15 mL) and pyridine (1.6 mL) was treated with ethyl chloroformate (0.7 g, 4.8
mmol) at 0 °C under argon. After the addition was finished reaction was stirred at room
temperature for 12 h and then diluted with more dichloromethane. The resultant solution was
washed with IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over
anhydrous sodium sulfate, the solvent evaporated to yield light yellowoil. This crude product was
purified by flash column chromatography and recrystallised from hexane to get white crystalline
solid of title compound.
[0241] Melting point :100°C
[0242] IR (cm-1) : 3341 (N-H), 2919 (C-H), 1698 (C=O)
[0243] Mass (Electrospray): 587 (M+1), 585 (M-1)
[0244] 'H NMR (5 ppm) : 8.3 (bs, 1H, D20 exchangeable, N-H) 7.2 (t, J=8 Hz, 1H,
aromatic proton) 6.85 (d, J=8Hz, 1H, aromatic proton) 6.7 (d, J=8Hz, 1H, aromatic proton) 6.57 (s,
1H, Q-H) 5.0 (m, 1H, OCH(CH3)2) 4.25 (q, 2H, J=6 Hz, 0-CH2) 3.75 (s, 3H, 0-CH3) 3.2 (m, 1H,
benzylic) 3.0 (m, 1H, benzylic) 2.25 (s, 3H, allylic) 1.9-1.0 (m, 35H, (CH2),3 from alkyl chain, CH3,
(CH3)2) 0.87 (dt, 3H, terminal CH3 from alkyl chain).
[0245] bs-broad singlet, t-triplet, d-doublet, s-singlet, m-multiplet, dt-distorted triplet

[0246] The solution of 1,4-dihydro-2-[[(4-methoxyphenyl)methyl)oxy]-6-meihyl-4-[2-
ethoxy-6-peatadecylphenyl]-5-pyrimidinecarboxylic acid methyl ester (3 g, 4.7 mmol) in
dichloromethane (15 mL) and pyridine (1.5 mL) was treated with ethyl chloroformate (0.7 g, 4.8
mmol) at 0 °C under argon. After the addition was finished reaction was stirred at room
temperature for 12 h and then diluted with more dichloromethane. The resultant solution was
washed with IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over
anhydrous sodium sulfate, the solvent was evaporated to yield light yellow oil. This crude product
was purified by flash column chromatography and recrystallised from hexane to get white
crystalline solid of title compound.
[0247J Melting point : 103 °C
[0248J DR. (cm"1) : 3346 (N-H), 2918 (C-H), 1698 (OO)
[0249] Mass (Electrospray): 573 (M+1), 571 (M-1)
(02501 'H NMR (5 ppm) : 7.4 (bs, 1H, N-H) 7.15 (t, J= 7Hz, 1H, aromatic proton)
6.85 (d,J=8Hz, 1H, aromatic protoh)U^
2H, 0-CH2 ) 4.0 (q, 2H, J= 6Hz, 0-CH2) 3.6 (s, 3H, O-CH3) 3.15 (m, 1H, benzylic) 2.95 (m, 1H,
benzylic) 2.28 (s, 3H, allylic) 1.85-1.0 (m, 32H, (CH2)i3 from alkyl chain, CH3, CH3) 0.9 (dt, 3H,
terminal CH3 from alkyl chain).
[0251] bs-broad singlet, t-triplet, d-doublet, s-singlet, m-multiplet, dt-distorted triplet, q-
quartet.

- [0252] The solution of 1,4-dihydro-2-[[(4-methoxyphenyl)methyl)oxy]-6-methyl-4-[2-
ethoxy-6-pentadecylphenyl]-5-pyrimidinecarboxylic acid ethyl ester (3 g, 4.65 mmol) in
dichloromethane (15 mL) and pyridine (1.5 mL) was treated with ethyl chlorofonnate (0.7 g, 4.7
mmol) at 0 °C under argon. After the addition was finished reaction was stirred at room
temperature for 12 h and then diluted with more dichloromethane. The resultant solution was
washed with IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over
anhydrous sodium sulfate, the solvent was evaporated to yield light yellow oil. This crude product
was purified by flash column chromatography and recrystallised from hexane to get white
crystalline solid of title compound.
[0253] Melting point :112°C
[0254] IR (cm'1) : 3342 (N-H), 2920 (C-H), 1697 (OO)
[0255] Mass (Electrospray): 587 (M+1), 585 (M-1)
[0256] 'H NMR (8 ppm) : 7.25 (bs, 1H, N-H) 7.15 (t, J= 7Hz, 1H, aromatic proton)
6.85 (d, J=8Hz, lH^aromatic proton) 6.7 (d, J=8Hz, 1H, aromatic proton) 6.6 (s, 1H, QrH) 4.2 (in,
6H, 0-CH2 ) 3.2 (m, 1H, benzylic) 2.95 (m, 1H, benzylic) 2.3 (s, 3H, allylic) 1.85-1.15 (m, 32H,
(CH2)i3 from alkyl chain, CH3, CH3, CH3) 0.9 (dt, 3H, terminal CH3 from alkyl chain).
[0257] bs-broad singlet, t-triplet, d-doublet, s-singlet, m-multiplet, dt-distorted triplet,
q-quartet.
[0258] The solution of 1,4-dihydro-2-[[(4-methoxyphcnyl)meihyl)oxy]-6-methyl-4-[2-
ethoxy-6-pentadecylphenyl]-S-pyrimidinecarboxylic acid isopropyl ester (3 g, 4.8 mmol) in
dichlorometbane (15 mL) and pyridine (1.5 mL) was treated with ethyl chloroformate (0.7 g, 4.8
mmol) at 0 °C under argon. After the addition was finished reaction was stirred at room
temperature for 12 h and then diluted with more dichloromethane. The resultant solution was
washed with IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over
anhydrous sodium sulfate, the solvent was evaporated to yield light yellow oil. This crude product
was purified by flash column chromatography and recrystallised from hexane to get white
crystalline solid of title compound.
[02591 Melting point : 110-111 °C
[0260J EL (cm-1) : 3350 (N-H), 2920 (C-H), 1696 (OO)
[0261] Mass (Electrospray): 601 (M+1), 599 (M-1)
[0262] 1H NMR (8 ppm) : 7.15 (m, 2H, D20 exchangeable for 1H, N-H, aromatic
proton) 6.8 (d, J=8HzTlH, aromatic proton) 6.6 (d, J=8Hz, 1H, aromatic proton) 6.5 (s, 1H, C6-H)
5.0 (m, 1H, OCH(CH3)3) 4.25 (m, 2H, CH2 ) 4.0 (q, 2H, 0-CH2) 3.25 (m, 1H, benzylic) 3.0 (m, 1H,
benzylic) 2.3 (s, 3H, allylic) 1.85-1.0 (m, 38H, (CH2)13 from alkyl chain, (CH3)2, CH3, CH3) 0.9 (dt,
3H, terminal CH3 from alkyl chain).
[0263] bs-broad singlet, t-triplet, d-doublet, s-singlet, m-multiplet, dt-distorted triplet,
q-quartet
[0264] The solution of 1,4-dihydro-2-[[(4-methoxyphenyl)methyl)oxy]-6-methyl-4-[2-
isopropoxy-6-pentadecylphenyl]-5-pyrimidinecarboxylic acid methyl ester (3 g, 4.7 mmol) in
dichloromethane (15 mL) and pyridine (1.5 mL) was treated with ethyl chloroformate (0.7 g, 4.8
mmol) at 0 °C under argon. After the addition was finished reaction was stirred at room
temperature for 12 h and then diluted with more dichloromethane. The resultant solution was
washed with IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over
anhydrous sodium sulfate, the solvent was evaporated to yield light yellow oil. This crude product
was purified by flash column chromatography and recrystallised from hexane to get white
crystalline solid of title compound.
[0265] Melting point : 120-121 °C
[0266] DR. (ran1) : 3342 (N-H), 2921 (C-H), 1670 (C=O)
[0267] Mass (Electrospray): 587 (M+1), 585 (M-1)
[0268] 'H NMR (8 ppm) : 7.85 (bs, 1H, N-H) 7.15 (t, J= 7Hz, 1H, aromatic proton)
6.8 (d, J=8Hz, 1H, aromatic proton) 6.7 (d, J=8Hz, 1H, aromatic proton) 6,55 (§, 1H, Cg-H) 4.65
(m, 1H, OCH(CH3)2) 4.2 (q, 2H, J= 6Hz, 0-CH2) 3.6 (s, 3H, 0-CH3) 3.0 (m, 2H, benzylic) 2.28 (s,
3H, allylic) 1.95-1.0 (m, 35H, (CH2)13 from alkyl chain, (CH3)2, CH3) 0.85 (dt, 3H, terminal CH3
from alkyl chain).
[0269] bs-broad singlet, t-triplet, d-doublet, s-singlet, m-multiplet, dt-distorted triplet,
q-quartet
[0270] The solution of 1,4-dihydro-2-[[(4-methoxyphenyl)methyl)oxy]-6-methyl-4-[2-
emoxy-6-pentadecylphenyl]-5-pyrirridmecarboxylic acid ethyl ester (3 g, 4.6 mmol) in
dichloromethane (15 mL) and pyridine (1.5 mL) was treated with ethyl chloroformate (0.8 g, 4.7
mmol) at 0 °C under argon. After the addition was finished reaction was stirred at room
temperature for 12 h and then diluted with more dichloromethane. The resultant solution was
washed with IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over
anhydrous sodium sulfate, the solvent was evaporated to yield light yellow oil. This crude product
was purified by flash column chromatography and recrystallised from hexane to get white
crystalline solid of title compound.
[0271] Melting point : 90-92 °C
[0272] IR (cm1) : 3340 (N-H), 2920 (C-H), 1696 (C=O)
[0273] Mass (Electrospray): 601 (M+1), 599 (M-1)
[0274] 1HNMR (8 ppm) : 7.6 (bs, 1H, N-H) 7.15 (dt, 1H, aromatic proton) 6.8 (d,
J=8Hz, 1H, aromatic proton) 6.7 (d, J=8Hz, 1H, aromatic proton) 6.55 (s, 1H, C6-H) 4.65 (m, 1H,
OHC(CH3)2) 4.1 (m, 4H, O-CH2) 3.15 (m, 1H, bertzylic) 2.95 (m, 1H, benzylic) 2.2 (s, 3H, allylic)
1.9-1.0 (m, 38H, (CH2)13 from alkyl chain, CH3, CH3, (CH3)2) 0.9 (dt, 3H, terminal CH3 from alkyl
chain).
[0275] bs-broad singlet, t-triplet, d-doublet, s-singlet, m-multiplet, dt-distorted triplet,
q-quartet.
[0276] The solution of 1,4-dihydro-2-[[(4-methoxyphenyl)methyl)oxy]-6-methyl-4-[2-
emoxy-6-pentadecylphenyl]-5-pyrimidmecarboxylic acid isopropyl ester (3 g, 4.5 mmol) in
dichloromethane (15 mL) and pyridine (1.5 niL) was treated with ethyl chloroformate (0.85 g, 4.6
mmol) at 0 °C under argon. After the addition was finished reaction was stirred at room
temperature for 12 h and then diluted with more dichloromethane. The resultant solution was
washed with IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over
anhydrous sodium sulfate, the solvent was evaporated to yield light yellow oil. This crude product
was purified by flash column chromatography and recrystallised from hexane to get white
crystalline solid of title compound.
[0277] Melting point : 88-90 °C
[0278] IR (cm1) : 3340 (N-H), 2918 (C-H), 1695 (C=O)
[0279] Mass (Electrospray): 615 (M+1), 613 (M-1)
[0280] 'H NMR (8 ppm) : 7.7 (bs, 1H, N-H) 7.17 (dt, 1H, aromatic proton) 6.8 (d,
J=8Hz, 1H, aromatic proton) 6.7 (d, J=8Hz,;1H, aromatic proton) 6.5 (s, 1H, Q-H) 5.0 (m, 1H,
OHC(CH3)2) 4.7 (m, 1H, OHC(CH3)2) 4.23 (q, J= 6Hz, 2H, O-CH2) 3.2 (m, 1H, benzylic) 3.0 (m,
1H, benzylic) 2.25 (s, 3H, allylic) 1.9-1.0 (m, 41H, (CH2)i3 from alkyl chain, CH3, (CH3)2, (CH3)2)
0.9 (dt, 3H, terminal CH3 from alkyl chain).
[0281] bs-broad singlet, t-triplet, d-doublet, s-singlet, m-multiplet, dt-distorted triplet,
q-quartet.
[0282] The solution of 1,4-dihydro-2-[[(4-memoxyphenyl)memyl)oxy]-6-(2'-
mercapto-1'H-benzimidazolyl)memyl-4-(2-memoxy-6-pentadecylphenyl]-pyrimidinecarboxylic
acid ethyl ester (3 g, 4.9 mmol) in dichloromethane (15 mL) and pyridine (2.0 mL) was treated
with ethyl chloroformate (0.7 g, 4.9 mmol) at 0 °C under argon. After the addition was finished
reaction was stirred at room temperature for 12 h and then diluted with more dichloromethane. The
resultant solution was washed with IN hydrochloric acid, water, sodium bicarbonate and brine.
After drying over anhydrous sodium sulfate, the solvent was evaporated to yield light yellow oil.
This crude product was purified by flash column chromatography to obtain the title compound.
[0283] m. (cm1) : 3450 (N-H), 2921 (C-H), 1686 (OO)
[0284] Mass (Electrospray): 721 (M+1), 719 (M-1)
[028S] 'H NMR (8 ppm) : 8.5 (bs, 1H, D20 exchangeable, N-H) 7.7 (d, J=6 Hz, 1H,
Aromatic proton) 7.5 (m, 1H, Aromatic proton) 7.25 (m, 2H, Aromatic proton) 7.15 (t, J=8 Hz, 1H,
Aromatic proton) 6.85 (d,J=8Hz,2H, Aromatic proton) 5^.(s,JH,C^H) 4.6 (s,1H,D2O
exchangeable, N-H) 4.5 (s, 2H, S-CH2) 4.0 (m, 3=6 Hz, 4H, O-CH2) 3.7 (s, 3H, O-CH3) 3.1 (m, 1H,
benzylic) 2.5 (m, 1H, benzylic) 1.85-1.1 (m, 35H, (CH2),3 from alkyl chain, CH3, CH3, allylic CH3)
0.9 (dt, 3H, terminal CH3 from alkyl chain).
[0287] The solution of 1,4-dihydro-2-([(4-methoxyphenyl)methyl)oxy]-6-methyl-4-[2-
isopropoxy-6-pentadecylphenyl]-5-pyrimidinccarboxylic acid methyl ester (3 g, 4.8 mmol) in
dichloromethane (15 mL) and pyridine (1.5 mL) was treated with ethyl chloroformate (0.7 g, 4.8
mmol) at 0 °C under argon. After the addition was finished reaction was stirred at room
temperature for 12 h and then diluted with more dichloromethane. The resultant solution was
washed with IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over
anhydrous sodium sulfate, the solvent was evaporated to yield light yellow oil. This crude product
was purified by flash column chromatography to obtain the title compound.
[0288] IR (cm"1) : 3352 (N-H), 2921 (C-H), 1692 (C=O)
[02891 Mass (Electrospray): 573 (M+1), 571 (M-1)
1H NMR (8 ppm) : 8.0 (bs, 1H, E^O exchangeable, N-H) 7.1 (t, J=8 Hz, 1H,
aromatic proton) 6.95 (d, J=8Hz, 1H, aromatic proton) 6.8 (d, J=8Hz, 1H, aromatic proton) 6.65 (s,
1H, OH) 4.0 (s, 3H, COOCH3) 3.75 (s, 3H, N-COOCH3) 3.0 (m, 1H, benzylic) 2.85 (m, 1H,
benzylic) 2.2 (s, 3H, allylic) 1.85-1.1 (m, 32H, (CH2)i3 from alkyl chain, (CR3h) 0.9 (dt, 3H,
terminal CH3 from alkyl chain).

[0292] The solution of 1,4^ihydro-2-[[(4-memoxyphenyl)methyl)thio]-6-methyl-4-[2-
memoxy-6^pentadecylphenyl]-5-pyrimidmecarboxylic acid ethyl ester (3 g, 4.7 mmol) in
dichloromethane (15 mL) and pyridine (1.5 mL) was treated with ethyl chloroformate (0.6 g, 4.7
mmol) at 0 °C under argon. After the addition was finished reaction was stirred at room
temperature for 2 h and then diluted with more dichloromethane. The resultant solution was
washed with IN hydrochloric acid, water, sodium bicarbonate and brine. After drying over
anhydrous sodium sulfate, the solvent evaporated to yield light yellow oil. This was dissolved in
dichloromethane (20 mL) and treated with trifloro acetic acid (2.0 mL) and ethanethioj (1.0 mL).
The reaction was stirred at room temperature overnight, and the solvent was evaporated and the
crude product was purified by flash column chromatography to obtain the title compound.
[0293] m.(cm-') : 3350 (N-H), 2921 (C-H), 1696 (C=O)
[0294] Mass (Electrospray): 589 (M+1), 587 (M-1)
[0295] 1H NMR (8 ppm) : 7.6 (bs, 1H, D20 exchangeable, N-H) 7.1 (t, J=8 Hz, 1H,
aromatic proton) 6.8 (d, J=8Hz, 1H, aromatic proton) 6.65 (d, J=8Hz, 1H, aromatic proton) 6.5 (s,
1H, C6-H) 4.05 (m, 4H, O-CH2) 3.7 (s, 3H, O-CH3) 3.05 (m, 1H, benzylic) 2.95 (m, 1H, benzylic)
2.2 (s, 3H, allylic) 1.85-1.1 (m, 32H, (CH2),3 from alkyl chain, CH3, CH3) 0.9 (dt, 3H, terminal CH3
from alkyl chain).
[0296] bs-broad singlet, t-triplet, d-doublet, s-singlet, m-multiplet, dt-distorted triplet
Example 48: Expression of T-tvpe channels in Mammalian Cells.
[0297] T-type calcium channels (ctlG) were stably expressed in HEK293 cells and
maintained at 37 °C in DMEM. Cells were released from dishes using trypsin and EGTA or
Accutase and studied within 4 hours of isolation. Individual cells were placed on the stage of an
inverted microscope and patched with pipettes pulled from aluminasilicate glass capillary tubes,
which had resistances of 0.8 -1.5 Mohm. Currents were recorded using an Axopatch 200 (Axon
Instruments, Inc.) and pClamp data acquisition software (8.1). The pipette solution contained (in
mM): KC1130, EGTA 11, HEPES 10, MgATP 5, pH = 7.4. The bath solution contained (in mM):
NaCl 140, CaCl2 1, HEPES 10, pH = 7.4. Test compounds were diluted into bath solution to the
desired concentration (100 nM - 10 uM) from a stock solutions (3 or 10 mM in DMSO). Current
measurements were made at 20 - 23 °C. Cells were held at -110 mV in order to maximize
occupancy in the closed state and depolarized for 100 ms to various potentials. Currents were
capacity corrected using 16-64 subthreshold responses (voltage steps of 10 or 20 mV) and leak
subtracted, based on linear interpolation between the current at the holding potential and 0 mV.
Cells were moved from a control chamber to a chamber with test compound and the effect of the
drug was assessed using a voltage clamp protocol that stepped-to -30 mV- for 100 ms from a
holding potential of-110 mV once every 5 s. After each 10-13 minutes, the train protocol was
interrupted and a full current voltage relationship obtained. In general for each compound, four
cells were studied for a minimum of 13 minutes, two in drug at 500 nM and two at 1 pM. In some
cases other concentrations were also studied. Data were analyzed using .Matlab (Mathworks,
Natick, MA). Drug efficacy was estimated using the relationship:
Blocked Fraction = [Drug] / (IC50 + [Drug])
[0298] The time course of block by drug was fit to a single exponential function:
Peak Current = A * exp (-t/x) + B
where A is the initial amplitude of the current, B the final level, t the time after the cell was
exposed to drug, and x, the time constant, i.e. the time it took for the current to be reduced to within
1/e of its final value, B. In general, modification ts are influenced both by drug on rate and off
rate, although washout was achievable for only one compound, so off rates are so slow (small) that
x can be taken to essentially represent 1/kon. For some compounds despite the presence of the drug
in the chamber, modification occurred with a delay. This was quantified from the time
modification was first observed.
Example 49: Block Studies.
[0299] To study block by PPK compounds, cells were held at a sufficiently negative
potential that under all ionic conditions studied, channels were fully available (approximately -
100mV). Cells were lifted from the chamber bottom and transferred to a second chamber in which
solutions with various concentration of drugs were flowing. Reversal of action was achieved by
transferring the cell back to the drug-free chamber. Figures show sample current traces obtained
during drug wash-in and wash-out (if any) with the time course of the change in peak current
displayed below. The cells was depolarized to -30 mV, once every 10 s until current magnitude in
drug stabilized. This low frequency of stimulation was chosen to avoid accumulation of channels in
an inactivated conformation.
Example 50: Animal Studies.
[0300] Fifteen male spontaneously hypertensive rats (SHR) were used in these
studies. The animals were 12 weeks old at arrival and 15 weeks old at the start of study. The
animals were divided into five groups, with three animals in each group. The starting, baseline
systolic blood pressure for all animals included in the study was 190-220 mmHg. The animals
were housed in contact bedding. They were fed Purina 5008. Six days after arrival, the animals
were trained in the blood pressure apparatus for four days before the start of the study.
[0301] Compounds were administered to the animals by tail vein injection. Dose
levels were 0.5 mL. In each study, one group of animals served as control, while the others .were
injected with a dosage of a compound.
[0303] References:
Methods of testing for pharmacological activities of the compounds:
1. Against calcium T-type channels (low voltage activated calcium channels):
a) L. Lacinova, N. Klugbauer, F. Hofmann "Regulation of the calcium channel a1G subunit by
divalent cations and organic blockers" Neuropharmacology, 39,1254-1266 (2000).
b) J. P. Clozel, E. A. Ertel, S.I. Ertel "Discovery and main pharmacological properties of
mibefradil (Ro 40-5967), the first selective T-type calcium channel blocker" Journal of
hypertension 15, S17-S25 (1997).
c) G. Mehrke, X. G. Zong, V. Flockerzi, F. Hofmann "The Ca2+ channel blocker Ro 40-5967
blocks differently T-type and L-type Caz+ channels" Journal of Pharmacology and
Experimental Therapeutics, 271,1483-1488 (1994).
d) S. Richard, S. Diochot, J. Nargeot, M. Baldy-Moulinier, J. Valmier "Inhibition of T-type
calcium currents by dihydropyridines in mouse embryonic dorsal root ganglion neurons"
Neuroscience Letters 132,229-234 (1991).
e) R. S. L Chaung, H. Jaffe, L. Cribbs, E. Perez-Reyes, K. J. Swartz "Inhibition of T-type
voltage gated calcium channel by a new scorpion toxin" Nature Neuroscience, 1, 668-674
(1998).
2. Against calcium L-type channels (high voltage activated calcium channels):
a) B. Z. Peterson, C. D. DeMaria, D. T. Yue "Calmodulin is the Ca2+ sensor for Ca2+-
dependent inactivation of L-type calcium channels" Neuron, 22, 549-558 (1999).
b) G. C. Rovnyak, S. D. Kimball, B. Beyer, G. Cucinotta, J. D. DiMarco, J. Gougoutas, A.
Hedberg, M. Malley, J. P. McCarthy, R. Zhang, S. Moreland "Calcium Entry Blockers and
Activators: Conformational and Structural Determinants of Dmy^opyrirnidine Calcium
Channel Modulators" Journal of Medicinal Chemistry, 38,199-129 (1995).
3. Against N-, P/Q-, and R- types of calcium channels:
a) Stea, A.; Soong, T. W.; Snutch, T. P. "Voltage gated calcium channels," in Handbook of
Receptors and Cltanneh; Ligand- and Voltage-Gated Ion Channels (North RA ed.), 1995,
113-152, CRC Press Inc., Boca Raton, Florida.
b) Zamponi, G. W. "Antagonist sites of voltage dependent calcium channels," Drug
Development Research. 1997,42,131-143.
c) Neelands, T. R.; King, A. P.; Macdonald, R. L. "Functional expression of L-, N-, P/Q-,
and R-type calcium channels in the human NT2-N cell line," J. Nenrophysiol. 2000, 84(6),
393-401.
CONCLUSION
[0304] Thus, those of skill in the art will appreciate that the compounds and uses
disclosed herein can be used as calcium channel blockers, providing a therapeutic effect.
[0305] One skilled in the art will appreciate that these methods and compounds are
and may be adapted to carry out the objects and obtain the ends and advantages mentioned, as well
as those inherent therein. The methods, procedures, and compounds described herein are presently
representative of preferred embodiments and are exemplary and are not intended as limitations on
the scope of the invention. Changes therein and other uses will occur to those skilled in the art
which are encompassed within the spirit of the invention and are defined by the scope of the
claims.
[0306] It will be apparent to one skilled in the art that varying substitutions and
modifications may be made to the invention disclosed herein without departing from the scope and
spirit of the invention.
[0307] Those-skilled in the art recognize that the aspects and embodiments of the
invention set forth herein may be practiced separate from each other or in conjunction with each
other. Therefore, combinations of separate embodiments are within the scope of the invention as
claimed herein.
[0308] All patents and publications mentioned in the specification are indicative of
the levels of those skilled in the art to which the invention pertains.
[0309] The invention illustratively described herein suitably may be practiced in the
absence of any element or elements, limitation or limitations which is not specifically disclosed
herein. Thus, for example, in each instance herein any of the terms "comprising", "consisting
essentially of and "consisting of may be replaced with either of the other two terms. The terms
and expressions which have been employed are used as terms of description and not of limitation,
and there is no intention that in the use of such terms and expressions indicates the exclusion of
equivalents of the features shown and described or portions thereof. It is recognized that various
modifications are possible within the scope of the invention claimed. Thus, it should be
understood that although the present invention has been specifically disclosed by preferred
embodiments and optional features, modification and variation of the concepts herein disclosed
may be resorted to by those skilled in the art, and that such modifications and variations are
considered to be within the scope of this invention as defined by the appended claims.
[0310] In addition, where features or aspects of the invention are described in terms of
Markush groups, those skilled in the art will recognize that the invention is also thereby described
in terms of any individual member or subgroup of members of the Markush group. For example, if
X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X
being bromine and claims for X being bromine and chlorine are fully described.
[0311] Other embodiments are within the following claims.
WE CLAIM:
1. A pharmaceutical composition for inhibiting T-channel
activity comprising a compound selected from compound
of formula I and formula II
Or a pharmaceutically acceptable salt, wherein
a) R1-R8 are each independently selected from the
group consisting of hydrogen;, halogen,
perhaloalkyl, nitro, amino a diazo salt,
optinally substituted lower alkyl, optionally
substituted lower alkylene and optinally
substituted five-membered or optionally
substituted six-membered heteroaryl ring or
optionally substituted six-membered aryl or
heteroaryl ring,
Where the lower alkyl and the lower alkylene moieties
are each independently and optionally substituted with
one or mire substituents selected from the group
consisting of consisting of halogen, perhaloalkyl,
nitro amino, hydroxy, alkoxy, sulfhudryl, thioether,
cyano, amido ester and
Where A is selected from the consisting of oxygen,
sulfur, and and -NH and R11 is selected for the group
consisting of hydrogen, hydroxy, alkoxy, haloalkoxy,
halogen, haloalkyl, nitro, and a diaxo salt, and n is
between 0-4; and
Where the ring moieties are each independently and
optionally substituted with one or more substituted
selected from the group consisting of lower alkyl,
lower alkylene,
b) R5 is selected from the group consisting of
hydrogen, alkyl, alkylen, and a five-membered or
six-membered heteroaryl ring or a six-membered
aryl or heteroaryl ring, optionally substituted
with one or more substituted selected from the
group consisting of lower alkyl, lower alkylene,
halogen, perhaloalkyl, nitro amino, cyano,
amido, and ester;
c) R10 is selected from the group consisting of
hydrogen and lower alkyl, or that R10 is
optionally not present, in present, in which
case the nitrogen-containing ring in the
compound of Formula I is pyridine;
d) R11-R13 and R15- R18 are each independently selected
from the group consisting of hydrogen, halogen,
perhaloalkyl, nitro, amino, a diazo salt,
optionally substituted lower alkyl, alkoxy,
optionally substituted lower alkylene and
optionally substitute five-membered or
optionally substituted six-membered heteroaryl
ring or optionally substituted six-membered aryl
or heteroary ring, wherein
Said lower alkyl and said lower alkylene
moieties are each independently and
optionally substituted with one or more
substituted selected from the group
consisting of halogen, perhaloalkyl, nitro,
amino, hydroxy alkoxy, sulfhydryl,
theirther, cyano, amido, ester,and

A is selected from the group of oxygen,
sulfur, sulfoxide, sulfone and -NH;
R22 is selected from the group consisting of
hydrogen, hydroxy, alkoxy, haloalkoxy,
halogen, haloallkyl, perhaloalkyl, nitro,
amino, and a diazo salt; n is between 0-
4; and
Said ring moieties are each independently an
optionally substituted with one or more
substituted selected from the group
consisting of lower alkyl, lower alkylene,
e) R19 is selected from the group consisting of
hydrogen, alkyl, alkylene, and a five-membered
or six-membered heteroary ring or a six-membered
aryl or heteroary ring, optionally substituted
with one or more substitutents selected from the
group consisting of lower alkyl, lower alkylene,
halogen, perhaloalkyl, nitro amino cyano, amido,
and ester; and
f) R20 is selected from the group consisting of
hydrogen and lower alkyl
g) R21 is selected from the group consisting of:
i) hydrogen, alkyl, alkoxy, alkylene, and a
five-membered or six-membered heteroaryl
ring or six-membered aryl or heteroaryl
ring optionally substituted with one or
more substituents selected from the group
consisting of lower alkyl,lower alkylene,
halogen, perhaloalkyl, nitro, amino,
cyano, amido, and ester;
ii) COY wherein Y is C1-C8 alkoxy or NR13R14,
wherein R13 is hydrogen or C1-C8 alkyl and
R14 is hydrogen, C1-C8 alkyl, or C1-C14
phenalkyl;
iv) halogen, CF3, cyano, nitro, COONHR35
COON(R35)2 COOSO2R38, COONR35SO2N(R35)2,
CO2R35, COON(R35)2, COOSO2 N(R35)2, COOSO2 R38.
v) CONR25R26, wherein R25 is selected from the
group consisting of hydrogen alkyl,
cycloalkyl, aryl,or aryulalkyl and R26 is
selected from the group consisting of
hydrogen, alkyl, cycloalkyl, aryl, or
halosubstituted alkyl, or R25 and R26
taken together with the nitrogen atom to
which they are attached form 1-
pyrrolidinyl, 1-piperidinyl, 1-azepinyl,
4-morpholoinyl, 1-piperidinyl 4-
thiamorpholinyl, 1 piperazinyl, each of
which is optionally substituted with one
or more substituents selected from the
group consisting of alkyl, alkoxy,
alkylthio, halo, thrifloromethyl, or
hydroxy;
vi) Z, COOZ, OR C(0) (NH) wherein Z is
selected from the group consisting of
Wherein
A) p and q are each independently 0-10;
B) R30 is phenyl optionally substituted with one or more
substituents independently selected from group consisting
of halogen, CF3, cyano, nitro, N(R35)2 NR35CONR37,
NR35.CON(R37)2f NR35SO2R38, NR35S02N (R37)2, (CH2) 0-4CON (R35)2, (CH2)0-
4SO2R38, and C1-4 alkyl;
C) R31 iS selected from the group consisting of hydrogen
cyano, OR38, COOR35, CON(R35)2, and phenyl optionally
substituted with one or more substituents independently
selected from the group consisting of halogen, CF3 cyano,
nitro, N(R35)2 NR35CONR37, NR35CON (R37) 2 NR35S02R38, NR35SO2N(R37)2,
(CH2)o-4CON(R35)2, (CH2)0-4S02N(R35)2, (CH2) 0-4SO2R38, and C1-4 alkyl;
D) R35 and R37 are each independently selected from hydrogen,
C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-4 CF3; and
E) R38 is selected from the group consisting of hydrogen, C1-
8 alkyl, C3-8 cycloalkyl, and (CH2)0-4 CF3;
h) X is oxygen or sulfur; and
i) Q is oxygen or nitrogen; provided that when Q is
oxygen R13 does not exist and a physiologically
acceptable carrier or diluent.
2. The pharmaceutical composition as claimed in claim 1,
wherein the carrier is preferably dimethyl
sulfoxide(DMSO).
3. The pharmaceutical composition as claimed in claim 1,
wherein the diluent is preferably a phosphate buffered
saline.
4. The pharmaceutical composition as claimed in claim 3,
wherein the said compound is selected from the group
consisting of Diethyl 1, 4-dihydro-4-(2'-ethoxy-6'-
pentadecylphenyl)-2,6-dimethyl-3,5-pyridine
dicarboxylate;
Dimethyl 1,4-dihydro-4-(2'-ethoxy-6'-
pentadecylphenyl)-2,6-dimethyl-3,5-phyridine
dicarboxylate;
Diisopropyl 1,4-dihydro-4-(2'-ethoxy-6'-
pentadecylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate;
dimethyl 1,4-dihydro-4-(2'-isopropoxy-6'-pentadecylphenyl)-
2-methyl-6-methyl(5'-methyl-2-mercapto-l'H-
benzimidazoly)methyl-3, 5-pyridine dicarboxylate; and
diisopropyl 1,4-dihydro-4-(2'-isopropoxy-6'-
pentadecylphenyl)-2-methyl-6-methyl (5'-methyl-2-mercapto-
1'H-benzimidazolyl)methyl-3,5-pyridine dicarboxylate.
5. The pharmaceutical composition as claimed in claim 3,
wherein the compound is selected from the group
consisting of
5-ethoxycarbonyl-4-(2-ethoxy-6-pentadecylphenyl)-6-
(2'-mercapto-1'H-benzimidazolyl) methyl-3,4-
dihydropyrimidin-2(1H)-one,
5-ethoxycarbonyl-4-(2-methoxy-6-pentadecylphenyl)-6-
methyl-3,4-dihydropyrimidin-2(1H)-one,
5-methoxycarbonyl-4-(2-ethoxy-6-pentadecylphenyl)-6-
methyl-3,4-dihydropyrimidin-2(1H)-one,
5-methoxycaarbonyl-4-(2-methoxy-6-pentadecylphenyl)-6-
methyl-3,4-dihydropyrimidin-2(1H)-one,
5-ethoxycarbonyl-4-(2-ethoxy-6-pentadecylphenyl)-6-
methyl-3,4-dihydropyrimidin-2(1H)-one,
5-methoxycarbonyl-4-(2-methoxy-6-(8'Z, 11'Z, 14'Z)
pentadecatrienyl phenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one,
5-methoxycarbonyl-4-(2-methoxy-6-(8' Z, 11' Z)
pentadecadienyl phenyl)-6-methyl-3,4-dihydropyrimidin-
2(lH)-one,
5-methoxycaarbonyl-4-(2-methoxy-6-(8'z) pentadecenyl
phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one,
5-carboxamido-l-{N-[3-[4-(4-methoxycarbonyl)-4-
phenylpiperidin-1-yl] propyl] carboxamido}-4-methyl-6-[2-
methoxy-6-pentadecylphenyl]-2-oxo-l,2,3,6-
tetrahydropyrimidine, and
1-{N-[3-[4-(4-methoxycarbonyl)-4-phenylpiperidin-l-yl]
carboxamido}-4-methyl-5-(N-methylcarboxamido)-6-[2-methoxy-
6-pentadecylphenyl]-2-oxo-l,2,3,6-tetrahydropyrimidine.


The present invention is directed in part towards methods of modulating the function of calcium channels with dihy-dropyrimidine, dihydropyrimidone, dihydropyrimidinethione, and dihydropyridine compounds. In addition, the invention describes methods of preventing and treating protein kinase-related abnormal conditions in organisms with a compound identified by the invention. Furthermore, the invention pertains to T-channel agonists that have a slow onset of activity and long duration of activity.

Documents:

616-KOLNP-2005-(15-10-2012)-FORM-27.pdf

616-kolnp-2005-abstract.pdf

616-kolnp-2005-claims.pdf

616-kolnp-2005-correspondence 1.1.pdf

616-kolnp-2005-correspondence.pdf

616-kolnp-2005-description (complete).pdf

616-kolnp-2005-drawings.pdf

616-kolnp-2005-examination report 1.1.pdf

616-kolnp-2005-examination report.pdf

616-kolnp-2005-form 1.pdf

616-kolnp-2005-form 18 1.1.pdf

616-kolnp-2005-form 18.pdf

616-kolnp-2005-form 2.pdf

616-kolnp-2005-form 26 1.1.pdf

616-kolnp-2005-form 26.pdf

616-kolnp-2005-form 3 1.1.pdf

616-kolnp-2005-form 3.pdf

616-kolnp-2005-form 5 1.1.pdf

616-kolnp-2005-form 5.pdf

616-KOLNP-2005-FORM-27-1.pdf

616-KOLNP-2005-FORM-27.pdf

616-kolnp-2005-granted-abstract.pdf

616-kolnp-2005-granted-claims.pdf

616-kolnp-2005-granted-description (complete).pdf

616-kolnp-2005-granted-drawings.pdf

616-kolnp-2005-granted-form 1.pdf

616-kolnp-2005-granted-form 2.pdf

616-kolnp-2005-granted-specification.pdf

616-kolnp-2005-reply to examination report 1.1.pdf

616-kolnp-2005-reply to examination report.pdf

616-kolnp-2005-specification.pdf


Patent Number 243338
Indian Patent Application Number 616/KOLNP/2005
PG Journal Number 41/2010
Publication Date 08-Oct-2010
Grant Date 06-Oct-2010
Date of Filing 11-Apr-2005
Name of Patentee DIAKRON PHARMACEUTICALS, INC.
Applicant Address 4570 EXECUTIVE DRIVE, SUITE 100, SAN DIEGO CA
Inventors:
# Inventor's Name Inventor's Address
1 RAO, SRIRAMA 12132 OAKVIEW WAY, SAN DIEGO, CA 92128
2 BIBBS, JEFFREY, A. 13870 BRUYERE COURT, SAN DIEGO, CA 92129
PCT International Classification Number A61K 31/4422
PCT International Application Number PCT/US2003/028527
PCT International Filing date 2003-09-11
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/464,814 2003-04-21 U.S.A.
2 60/410,338 2002-09-12 U.S.A.